cardiovascular medicine

HEART FAILURE
Sachin P. Shah, MD, and Mandeep R. Mehra, MD*
Heart failure is a syndrome related to abnormal cardiac performance with a consequence of impaired cardiac output at
rest or with exertion and/or congestion, which usually leads
to symptoms of fatigue, dyspnea, and edema. The syndrome
is characterized by various phenotypes related to a vast array
of etiologies with diverse management targets. The current
broad categorization of heart failure separates patients as
having a reduced ejection fraction (typically < 0.40) or a
preserved ejection fraction (> 0.50; 0.400.50 represents an
intermediate group). Further description of the phenotype
beyond ejection fraction is imperative to correctly identify
the etiology of heart failure and, ultimately, to choose medical, device, and surgical therapies appropriately.
Epidemiology of Heart Failure
Based on data from the National Health and Nutrition
Examination Survey (NHANES), an estimated 5.7 million
adults in the United States have heart failure, and the prevalence is projected to increase by 46% over the next 15 years.1
Age and hypertension are the predominant risk factors for
the development of heart failure; at the age of 40 years, the
lifetime risk of developing heart failure is 1 in 5, and this risk
is doubled in those with a blood pressure greater than
160/90 mm Hg.2 Hypertension is an extremely potent risk
factor, with nearly three quarters of patients with heart failure
having a history of hypertension (defined as blood pressure
> 140/90 mm Hg). This risk is modifiable, as has been
demonstrated in several studies, but the optimal degree to
which blood pressure should be controlled to prevent heart
failure is unknown.3,4 Recent data from the Systolic Blood
Pressure Intervention Trial (SPRINT) in nondiabetics
demonstrated a 38% relative risk reduction (0.8% absolute
reduction at 3.26 years) in the development of heart failure
with an aggressive systolic blood pressure target of less than
120 mm Hg compared with a conventional target of less
than 140 mm Hg, yet optimal targets remain unclear, particularly in diabetic individuals.5 In 2012, the total cost of heart
failure in the United States was estimated to be $30.7 billion.1
Although the population of patients is heterogeneous, the
median survival of patients with preserved or reduced ejection fraction from the time of diagnosis is a dismal 5 years,
with recent data suggesting a declining mortality, largely
due to increased use of disease-modifying agents and better
blood pressure control.6
Defining the Phenotype and Etiology of
Heart Failure
There are various etiologies of heart failure; identifying
the correct etiology requires careful attention to the history,
*The authors and editors gratefully acknowledge the contributions of the previous author, Mariell Jessup, MD, to the development and writing of this chapter.

2016 Decker Intellectual Properties Inc

physical examination, basic laboratory analysis, electrocardiogram, and echocardiogram. Based on these initial data,
the need for further testing may be determined. The most
common cause of heart failure with a reduced ejection fraction (HFrEF) is coronary artery disease, or ischemic cardiomyopathy.7 Ischemic cardiomyopathy is usually related to
previous infarction rather than severe ongoing or repetitive
ischemia; however, there is a subset of patients with severe
myocardial ischemia and left ventricular systolic dysfunction secondary to hibernating myocardium. Patients with
left ventricular systolic dysfunction and risk factors for coronary artery disease should undergo coronary angiography
for evaluation, especially in the presence of angina, because
surgical revascularization in these patients may improve
outcomes.8 Adults without angina and without risk factors
may undergo a noninvasive coronary evaluation. Some
patients may have coronary artery disease that is less than
expected (or out of proportion) for the degree of left ventricular systolic dysfunction; these patients are more appropriately classified as a nonischemic cardiomyopathy with
bystander coronary artery disease. In such circumstances,
acceleration or instability of the bystander coronary arterial
disease may participate in the progression of the natural
history of the disease state and thus deserves to be an equal
therapeutic target for disease modification.
There are a variety of causes of nonischemic cardiomyopathy, which are listed here [see Table 1]. HFrEF that is not
related to myocardial infarction (MI) or ischemia may be
familial; related to previous myocarditis, previous toxin exposure (such as anthracycline chemotherapy or alcohol), sarcoidosis, or tachyarrhythmia; or from a number of other causes.
Heart failure with a preserved ejection fraction (HFpEF) is
typically associated with hypertension with at least mild left
ventricular hypertrophy, older age, diabetes, metabolic syndrome, and renal dysfunction. A small subset of patients
with HFpEF will have an infiltrative or storage disease
related cardiomyopathy, hypertrophic cardiomyopathy, or
constrictive pericarditis. Valvular heart disease may present
as HFpEF and should always be considered in the differential diagnosis.
Beyond basic transthoracic echocardiography, further
imaging studies may be directed by the clinical history and
findings on an echocardiogram. Cardiac magnetic resonance imaging (MRI) has excellent spatial resolution and,
with gadolinium contrast administration, has an excellent
ability to identify areas of myocardial scar. Occasionally,
cardiac MRI findings may suggest a particular etiology,
such as inflammation, infiltration, iron overload cardiomyopathy, or cardiac sarcoidosis. Fluorodeoxyglucose positron
emission tomography (FDG-PET) imaging may be useful as
well in identifying areas of inflammation in disease processes such as cardiac sarcoidosis, as well as for assessment
of coronary flow reserve, a finding with potential prognostic
utility.9
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heart failure 2

Table 1 Various Etiologies of Heart Failure

Ejection Fraction
Reduced EF

Preserved EF

Etiology

Comments

Specific Diagnostic Testing

Ischemic heart disease

Most often related to previous infarction; may

be related to resting ischemia or repetitive
episodes of ischemia

Coronary angiography preferred

(especially if any risk factors or
angina); noninvasive stress testing as
an alternative

Idiopathic dilated
cardiomyopathy

Designation when other causes have been

ruled out; many may be related to a genetic
predisposition

Exclude other causes

Familial
cardiomyopathy

Family history of cardiomyopathy, sudden

death, or arrhythmia

Genetic testing coupled with genetic

counseling

Valvular disease

Usually related to severe chronic valvular

disease

Often easily apparent on transthoracic

echocardiogram

Previous myocarditis

May be implicated more frequently than

occurs

No specific testing; viral antibody titers

are often unhelpful

Hyperthyroidism,
thyrotoxicosis

Often associated with atrial arrhythmias

Serum thyroid panel

Arrhythmogenic
right ventricular
cardiomyopathy

Classically involves the right ventricle but

may be biventricular or left dominant;
significant ventricular arrhythmias

Clinical diagnosis incorporating clinical,

ECG, and imaging findings (Revised
Task Force Criteria)

Cardiac sarcoidosis

May have a preserved or low EF. Patchy

involvement; may be associated with
extracardiac sarcoidosis or may be isolated
cardiac sarcoidosis. Associated with heart
block and arrhythmia.

Evaluation for extracardiac sarcoidosis

(most often with chest imaging for
pulmonary sarcoidosis evaluation);
cardiac MRI and cardiac FDG-PET
are helpful

Metabolic disorders

Low magnesium, calcium, and potassium;

thiamine deficiency; and glycogen storage
diseases

Connective tissue
disorder associated

Lupus and rheumatoid arthritis; cardiomyopathy is not often the presenting abnormality

Serum antibody testing (ANA, RF,

anti-CCP)

Tachycardia mediated

Can be caused by any tachyarrhythmia; often

atrial fibrillation; requires a ventricular rate
significantly over 100 beats per minute
likely for weeks

Retrospective diagnosis based on

improvement in ventricular function
with control of arrhythmia

Toxins

Cocaine (with or without infarct), alcohol

(usually reversible with alcohol cessation)

Heavy metals

Cobalt, chromium

Usually based on history; serum heavy

metal levels may be tested

Cancer chemotherapy

Anthracyclines most well studied (but many

chemotherapeutic agents may be cardiotoxic); dose related, although can occur at
any dose and may present even decades
after anthracycline therapy (although
development of systolic dysfunction is
almost always within the first year and may
be subclinical)

Diagnosis based on history and

excluding other common causes
(i.e., coronary artery disease)

Peripartum

Often reversible but may be severe and

occasionally requires cardiac transplantation (typically occurs within last month of
pregnancy or up to 5 months after delivery)

Muscular dystrophy

Becker, Duchenne, myotonic muscular

dystrophy

Serum creatine kinase

HIV related

Can occur in advanced HIV/AIDS

HIV antibody

High-output heart
failure

Related to Paget disease, large arteriovenous

fistula, or chronic severe anemia (after
prolonged period may lead to a reduction
in EF)

Hypertension

Myocardial hypertrophy related to long-standing

hypertension; may have dilated aorta

Diabetes

May also be associated with metabolic

syndrome; pathogenesis unclear

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heart failure 3

Table 1 Continued
Ejection Fraction

Etiology

Comments

Specific Diagnostic Testing

Hypertrophic
cardiomyopathy

Usually asymmetrical hypertrophy; may be

apical variant, often family history, and at
risk for arrhythmias and sudden death.
May have dyspnea related to left ventricular outflow tract obstruction requiring beta
blockers or calcium channel blockers; may
worsen with diuretics and vasodilators.

Imaging (echocardiography, cardiac

MRI) and genetic testing

Amyloidosis

Three major types may cause clinical heart

failure: AL (primary), light-chain
abnormality (treated with chemotherapy
stem cell transplantation), wild-type TTR
(senile age-related amyloidosis), and
mutant-type TTR (hereditary amyloidosis)

SPEP, UPEP, serum free light chains,

abdominal fat aspirate, biopsy of
target organ (heart, kidney),
technetium pyrophosphate scan,
cardiac MRI, genetic testing to detect
TTR mutation to differentiate from
wild-type and mutant-type TTR
amyloidosis

Hemochromatosis

May be a dilated or restrictive phenotype, may

be primary, related to a genetic abnormality
resulting in abnormal iron handling, or
secondary, related to repeated blood
transfusions

Transferrin saturation, ferritin, cardiac

MRI (T2* sequence), HFE gene testing
(autosomal recessive, responsible for
95% of hereditary hemochromatosis
in North America)

Endomyocardial fibrosis

Related to eosinophilia of any cause (Loeffler

endocarditis) or may be idiopathic

Eosinophil count, cardiac MRI,

endomyocardial biopsy

Storage diseases

Fabry, Dannon, Pompe, Gaucher

Constrictive pericarditis

May mimic a restrictive cardiomyopathy; most

commonly related to previous cardiac
surgery, pericarditis, or tuberculosis.
Potential cure with surgical pericardial
stripping.

Cardiac MRI and simultaneous left and

right heart catheterization may help
differentiate from restrictive
cardiomyopathy

Right heart failure

May mimic heart failure with a preserved EF;

most often related to pulmonary hypertension
(which may be related to left heart failure)

Right heart catheterization and

evaluation for pulmonary disease

ANA = antinuclear antibody; CCP = cyclic citrullinated peptide; ECG = electrocardiography; EF = ejection fraction; FDG-PET = fluorodeoxyglucose positron emission
tomography; MRI = magnetic resonance imaging; RF = rheumatoid factor; SPEP = serum protein electrophoresis; TTR = transthyretin; UPEP = urine protein electrophoresis.

Recognition and Management of Acute Decompensated

Heart Failure
clinical assessment of acute decompensated
heart failure
The clinical presentation of acute decompensated heart
failure (ADHF) may be variable with regard to the etiology,
the severity on presentation, and the presenting symptoms.
The symptoms resulting from ADHF typically relate to
resting- or exercise-related increases in left atrial pressure
and a reduction in systemic perfusion. The symptom profile
of patients reflects the severity of the various derangements
in ventricular filling pressures and cardiac output. Dyspnea
at rest or with minimal exertion correlates well with elevations in left atrial pressure and improves with therapy aimed
at reducing left atrial pressure.10 Orthopnea (dyspnea while
supine or supine cough) and paroxysmal nocturnal dyspnea
are symptoms consistent with elevations in left atrial and
pulmonary venous pressures, whereas peripheral edema and
symptoms related to visceral and abdominal swelling (increased
abdominal girth, early satiety, loss of appetite) are often
symptoms of elevations in right atrial and systemic venous
pressures. Physical findings of ADHF that relate to an
increase in right- and left-sided ventricular filling pressures
include elevated jugular venous pressure, hepatomegaly,

ascites, edema, an S3 on cardiac auscultation, and rales.11

Most physical findings have only a modest sensitivity and
specificity; however, rales have a notably low sensitivity of
only 15% and are uncommon in patients presenting with
ADHF [see Table 2].11 Patients presenting with ADHF may
have an adequate resting cardiac output or reduced cardiac
output that may be inadequate to meet the metabolic
demands of the body at rest; this may manifest as cool
extremities, altered mental status or decreased level of consciousness, a low urine output, and a narrow pulse pressure.
Patients exhibiting this hemodynamic profile have a worse
prognosis compared with those presenting with evidence of
an adequate cardiac output.12 Radiographic and laboratory
data may provide adjunctive support for the diagnosis of
ADHF or may offer an alternate diagnosis. Chest roentgenogram findings of cephalization, alveolar or interstitial
edema, and pleural effusions carry a high specificity but an
overall poor sensitivity for the diagnosis of ADHF.13 Serum
brain natriuretic peptide (BNP) and N-terminal probrain
natriuretic peptide (NT-proBNP) are biomarkers that reflect
left ventricular stretch and have an excellent negative predictive value with a modest positive predictive value. The
negative predictive values of a BNP value less than 50 pg/mL
and an NT-proBNP value less than 300 pg/mL are 96% and
97%, respectively, making these excellent tests to exclude

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heart failure 4

Table 2 Sensitivity and Specificity of Clinical, Biomarker,

and Radiographic Data in the Diagnosis of Acute Decompensated Heart Failure
Clinical, Biomarker and Radiographic Findings

Sensitivity (%)

Specificity (%)

Clinical symptoms
Orthopnea

29

81

Paroxysmal nocturnal dyspnea

27

84

JVP 12 cm H2O

65

64

Hepatojugular reflux

83

27

S3

62

32

Rales one third of lung fields

15

89

Hepatomegaly (> 4 fingerbreadths)

15

93

BNP ( 100 pg/mL)

90

76

NT-proBNP ( 900 pg/mL)

90

85

Interstitial edema

42

96

Alveolar edema

15

86

Pleural effusion

34

92

99

64

73

Physical findings*

Laboratory data

Radiographic data

Cephalization of vessels
Any abnormality

Physical findings based on data from Drazner MH et al11. NT pro-BNP and radiographic data from Martinez-Rumayor AAet al13; Maisel AS14. Clinical symptoms from Kelder JC, Cramer JM, van Wijngaarden J, et al. The diagnostic value of physical examination and additional testing in primary
care patients with suspected heart failure. Circulation 2011;124:286573.
BNP = brain natriuretic peptide; JVP = jugular venous pressure; NT = N terminal.
*Sensitivity and specificity of physical findings to detect pulmonary arterial wedge pressure of > 22 mm Hg.

the diagnosis of heart failure in the dyspneic patient, when

the diagnosis is in doubt.14,15 Exercise provocation using a
6-minute walk test or peak aerobic capacity evaluation by
metabolic testing may be useful in establishing the functional
status and assessing cardiac reserve.16
management of adhf
ADHF often results in hospital admission for rapid institution of intravenous diuretics, vasodilators, and possibly
positive inotropic agents, intubation for refractory hypoxia
is required in about 5% of patients.17 Hospitalization for
acute decompensation is an important marker for disease
severity and carries a high short-term (5 to 8% in-hospital)
and long-term mortality (20% at 1 year). Analysis of in-hospital
registries has identified several parameters associated with
worse outcomes: a blood urea nitrogen level greater than
43 mg/dL, systolic blood pressure less than 115 mm Hg, a
serum creatinine level greater than 2.75 mg/dL, and an elevated troponin I level.18,19
In concert with institution of medical therapy to relieve
symptoms, the clinician should also attempt to identify possible triggers for decompensation. Respiratory infection,
acute coronary syndrome, arrhythmia, hypertension, anemia,
thromboembolism, worsened renal function, and nonadherence to either diet or medications are potential triggers for
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decompensation.20 Interestingly, in-hospital mortality is

significantly lower for patients in whom heart failure was
precipitated by dietary or medication nonadherence or hypertension compared with respiratory infection or worsened
renal function.

Diuretics
The mainstay of ADHF management is intravenous
administration of diuretics, most often achieved with the use
of loop diuretics. Intravenous delivery is imperative given
impaired and variable oral drug absorption, which is most
prominent in the decompensated state when intestinal edema
may decrease the oral bioavailability of diuretics. When high
doses of diuretic agents are required, or when the effect is
suboptimal, a continuous infusion may be needed to reduce
toxicity and maintain stable serum drug levels. Randomized
clinical trials of high- versus low-dose or bolus versus continuous infusion of diuretics have not provided clear justification for the best diuretic strategy in ADHF, and as such,
the construct of an optimal diuretic regimen remains an art
rather than a science.21 The addition of a thiazide or thiazidelike diuretic agent such as metolazone or chlorothiazide in
combination with a loop diuretic provides a synergistic effect
and is often required in patients receiving long-term therapy
with loop diuretic agents.22 Thiazide diuretics occasionally

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may result in significant hypokalemia; therefore, potassium
levels should be monitored closely during administration.
Change in weight is often used as a surrogate for adequate
diuresis, but this objective measure of volume status may be
surprisingly difficult to interpret, and weight loss during
hospitalization does not necessarily correlate closely with
outcomes. It is generally advisable to continue diuresis until
euvolemia has been achieved. Physical examination findings, specifically normalization of the jugular venous pressure and resolution of edema, may be used as surrogate end
points for diuresis.
Renal dysfunction accompanies or complicates diuresis in
about 20 to 40% of patients hospitalized for ADHF.23 Mechanistic studies have been largely unable to find a correlation
between deterioration in renal function and reduced cardiac
output; in fact, most patients with cardiorenal syndrome
demonstrate a preserved cardiac output.24 In patients with
established heart failure, this syndrome may represent a
complex interplay of neurohormonal factors, potentially
exacerbated by backward failure resulting from increased
intra-abdominal pressure and impairment in return of renal
venous blood flow. Continued use of diuretic therapy may
be associated with a reduction in glomerular filtration rate
and a worsening of the cardiorenal syndrome when rightsided filling pressures remain elevated. In those patients in
the late stages of disease characterized by a profound low
cardiac output state, inotropic therapy or mechanical circulatory support (MCS) has been shown to preserve or improve
renal function in selected individuals in the short term until
more definitive therapy, such as durable MCS or cardiac
transplantation, is implemented.
Early experience with ultrafiltration, an invasive catheterbased technique to filter water and sodium directly out of
the circulation, suggested a potential role in patients with
renal dysfunction. The Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARRESS-HF) trial randomized 188 patients with ADHF and worsening renal failure to
stepped pharmacologic care or ultrafiltration.25 The primary
end point was a change in serum creatinine and a change in
weight (reflecting fluid removal) at 96 hours. Although similar
weight loss occurred in both groups (approximately 5.5 kg),
there was worsening renal function in the ultrafiltration group.
Death or rehospitalization for heart failure was no different
between groups, but there were more severe adverse events in
the ultrafiltration group, mainly due to renal failure, bleeding complications (as systemic anticoagulation is required to
prevent filter thrombosis), and intravenous catheter-related
complications. This investigation argues against using ultrafiltration as a primary strategy in patients with ADHF who
are responsive to diuretics, whether ultrafiltration is a viable
strategy in states of diuretic unresponsiveness is unknown,
and for this reason, this method of decongestion is used
judiciously and less commonly in clinical practice.
Inhibition of antidiuretic hormone with the oral selective
vasopressin-2 antagonist tolvaptan was evaluated in the
Efficacy of Vasopressin Antagonism in Heart Failure Outcome
Study with Tolvaptan (EVEREST) study, which did not
reveal any beneficial effects.26 Only a small subset of patients
(7.8% of the total 4,133) enrolled had hyponatremia (serum
sodium < 134 mEq/L). In these patients, the sodium level
increased by 5.5 mEq/L with tolvaptan compared with

heart failure 5
1.8 mEq/L with placebo by 7 days. Given the small size of
this subgroup, no differences in meaningful clinical end
points could be measured; thus, the treatment of hyponatremia as a primary target in decompensated heart failure
remains unclear.

Vasodilators
Vasodilators, including intravenous nitrates, nitroprusside,
and nesiritide (a recombinant BNP), have been advocated
for early therapy in an effort to stabilize ADHF. The latter
agent was introduced in a fixed-dose continuous infusion
after a comparison with intravenous nitrates suggested more
rapid and greater reduction in pulmonary capillary wedge
pressure. Enthusiasm for nesiritide waned due to concerns
within the pivotal trials for the development of renal insufficiency and an increase in mortality.27,28 To address these
concerns, a large-scale morbidity and mortality trial, the
Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), randomly enrolled
7,141 patients with ADHF to nesiritide or placebo for 24 to
168 hours in addition to standard care.29 Nesiritide was not
associated with an increase or a decrease in the rate of death
and rehospitalization and had a clinically insignificant benefit on dyspnea. Renal function did not worsen, but increased
rates of hypotension were noted. Although this trial established the safety for this drug, its routine use cannot be
advocated due to a lack of significant efficacy. Recombinant
human relaxin-2, or serelaxin, is a peptide upregulated in
pregnancy and examined in ADHF patients with a normal
or elevated blood pressure. In the RELAXin in Acute Heart
Failure (RELAX-AHF) trial, serelaxin or placebo was added
to a regimen of standard therapy in 1,161 patients hospitalized with ADHF, evidence of congestion, and systolic pressure greater than 125 mm Hg. Serelaxin improved dyspnea,
reduced signs and symptoms of congestion, and was associated with less early worsening of HF.30 Exploratory end
points of hard outcomes at 6 months suggested positive signals in favor of improved survival, which warrants further
examination. This drug is now being investigated in a largescale pivotal trial, RELAX-AHF2. The TRial of Ularitides
Efficacy and safety in patients with Acute Heart Failure
(TRUE-AHF) is a phase III clinical trial (> 2,000 patients)
designed to evaluate the efficacy and safety of ularitide, an
analogue of the natriuretic peptide urodilatin, as an intravenous infusion in addition to conventional therapy in patients
suffering from acute heart failure.31,32

Inotropic Agents
To effectively treat ADHF, the adequacy of the cardiac
output at rest must be determined. This can most often be
performed by a careful clinical assessment. The routine use
of a pulmonary artery catheter is not recommended in
ADHF and should be restricted to those who respond poorly
to attempts at diuresis or who demonstrate signs and symptoms suggestive of a low cardiac output with or without
hypotension (systolic blood pressure < 90 mm Hg).33 Immediate inotropic infusion should be instituted in those who
have significant impairment in neurologic or renal function
or lactic acidosis thought to be related to hypoperfusion.
Otherwise, inotropic therapy is often instituted in patients with
more subtle signs of hypoperfusion, such as cool extremities
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or a narrow pulse pressure, or those who fail initial aggressive
attempts at diuresis. Impairment of myocardial contractility
often accompanies ADHF, and pharmacologic agents that
increase intracellular concentration of cyclic adenosine monophosphate via direct or indirect pathways such as sympathomimetic amines (dobutamine) and phosphodiesterase-3
inhibitors (milrinone) serve as positive inotropic agents to
augment cardiac output. Their activity leads to an increase
in cytoplasmic calcium. Inotropic therapy in those with a
low-output state augments cardiac output, improves perfusion, and relieves congestion acutely.34 Although milrinone
and dobutamine have similar hemodynamic profiles, milrinone is slower acting and is renally excreted and thus
requires dose adjustments in the setting of renal impairment.
Of note, both inotropic agents demonstrate vasodilatory
properties such that dopamine, which has alpha1 agonist
properties, should be instituted at a starting dose of at least
5 g/kg/min in patients with a systolic blood pressure less
than 70 mm Hg.3 In patients with more mild degrees of
hypotension, dobutamine is likely a better option than milrinone given less vasodilation and a shorter halflife, which
allows for discontinuation and clearance of the drug if worsening hypotension is experienced.35 Novel inotropic agents
that leverage the concept of myofilament calcium sensitization
rather than increasing intracellular calcium levels have been
introduced. Levosimendan is a calcium sensitizer that provides
inotropic activity but also possesses phosphodiesterase-3
inhibition properties that result in vasodilation, making the
drug unsuitable in states of hypotension. Two trials have
tested this agent in ADHF. Survival of Patients with Acute
Heart Failure in Need of Intravenous Inotropic Support
(SURVIVE) compared levosimendan with dobutamine, and
despite an initial reduction in circulating BNP levels in the
levosimendan group compared with patients in the dobutamine group, this drug did not reduce all-cause mortality at
180 days or affect any secondary clinical outcomes.36 The
second Randomized Multicenter Evaluation of Intravenous
Levosimendan Efficacy (REVIVE II) compared levosimendan
against traditional noninotropic therapy and found a modest improvement in symptoms but worsened short-term
mortality and ventricular arrhythmias.37 Another agent,
omecamtiv mecarbil, a cardiac-specific myosin activator, has
shown promise in improving hemodynamic surrogates in
small trials and is being investigated in a larger clinical
study (Chronic Oral Study of Myosin Activation to Increase
Contractility in Heart Failure [COSMIC-HF]).38
abdominal contributions
Emerging evidence is refining an understanding of the role
of the splanchnic circulation and the abdominal compartment in heart failure. The abdominal organs and splanchnic
circulation appear to play an active role in volume distribution and renal filtration, thereby affecting balance between a
compensated and a decompensated state.39 The splanchnic
circulation accounts for about 25% of systemic blood flow
under normal circumstances and has the capacity to store a
significant amount of volume, which may allow for slow
subclinical volume retention that may lead to an increase in
abdominal pressure, even in the absence of ascites.40 Increased
abdominal pressure likely contributes to deterioration of
renal function and diminished sodium and water clearance,
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heart failure 6
which leads to a self-perpetuating deleterious cycle of volume
retention. The splanchnic venous capacitance appears to be
regulated in part by alpha1 (but not beta2) receptor stimulation and therefore leads to central redistribution of volume
in high adrenergic states. This redistributive increase in filling pressures appears to best respond to vasodilators and a
reduction in sympathetic drive. The understanding of the
homeostatic role of the abdominal compartment in the compensated state and the maladaptive role in the decompensated state is evolving and may provide targets for new
therapies and better application of available treatment strategies in the future.
Management of Chronic Heart Failure with
a Reduced Ejection Fraction
pharmacotherapy
The treatment of symptomatic heart failure has evolved
from a hemodynamic model targeting elevated ventricular
filling pressures and decreased cardiac output with diuresis
and inotropic therapy (including digoxin) to an era of disease
modification centered around neurohormonal antagonism.
Further opportunity in reversing the abnormal phenotype is
now being established and actively investigated with the
use of cardiac resynchronization therapy (CRT), cellular
therapy, and hemodynamic unloading [see Figure 1]. In this
regard, angiotensin-converting enzyme (ACE) inhibitors,
beta blockers, and aldosterone antagonists form the cornerstone of pharmacotherapy and lead to improvements in cardiac structure and function with consequent favorable
effects on heart failure symptoms, quality of life, burden of
hospitalization, and survival (both from heart failure and
arrhythmic deaths) [see Table 3]. Meta-analyses of several
randomized trials of ACE inhibitors in patients with heart
failure and an ejection fraction less than 40% suggest a 23%
reduction in mortality. On the background therapy of ACE
inhibitors, beta blockers have demonstrated an additional
35% reduction in mortality. Increased experience with both
agents in a broad range of patients with HFrEF has demonstrated the safety of ACE inhibitors in treating patients even
with mild renal insufficiency and the tolerability of beta
blockers in patients with moderately controlled diabetes,
asthma, and obstructive lung disease. The benefits of ACE
inhibitors and beta blockers extend to those with severe
symptoms (New York Heart Association [NYHA] classes III
to IV) and seem to be beneficial regardless of the etiology of
HFrEF. However, some patients with advanced heart failure
may not be able to achieve optimal doses of neurohormonal
inhibitors and require a cautious reduction in dose to maintain clinical stability. Such individuals with lower exposure
to ACE inhibitors and beta blockers represent a high-risk
cohort with a poor prognosis.
ACE inhibitors exert their beneficial effects in HFrEF as a
class; however, the beneficial effects of beta blockers are
thought to be limited to specific drugs. Beta blockers such as
bucindolol, or those with intrinsic sympathomimetic activity,
such as xamoterol, have not demonstrated a survival benefit.
On the basis of clinical trial data, beta-blocker use in HFrEF
should be restricted to carvedilol, bisoprolol, and metoprolol
succinate, agents that have been thoroughly tested in HFrEF
and proven to improve survival. Whether beta blockers or

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heart failure 7

Symptom
Relief

Prevention of
Disease
Progression

Renocentric
Model

Hemodynamic
Model

(DIURETICS)

(INOTROPES)

Neurohormonal Model
ACEI, ARB
Beta blockers
Aldosterone antagonists
ARNI
Nitric oxide pathway
Antiarrhythmic Model
(ICD)

Reversal of
Heart Failure
Phenotype?

Cardiac
Regeneration

Cardiac
Recovery

(Cell Therapy)

(CRT, MCS)

Figure 1 The evolution of therapy in chronic heart failure from the symptom-directed model, to disease modification strategies, to potential
reversal of the heart failure phenotype. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin
receptor neprilysin inhibitor; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter-defibrillator; MCS = mechanical circulatory
support.

ACE inhibitors should be started first was answered by the

Cardiac Insufficiency Bisoprolol Study (CIBIS) III, in which
outcomes did not vary when either agent was initiated
first.41 Thus, it does not appear to matter which agent is initiated first, but what is important is that optimally titrated
doses of both ACE inhibitors and beta blockers be established in a timely manner. The effects of both classes of
drugs appear to be dose dependent; therefore, it is important that ACE inhibitors and beta blockers be titrated to doses
achieved in clinical trials [see Table 4].
Patients enrolled in the three major aldosterone antagonist trials demonstrated an additional 15 to 34% relative risk
reduction in mortality in patients with an EF of less than 30
to 35% and symptomatic (NYHA class II to IV) heart failure
on a background medical therapy with ACE inhibitors and
beta blockers.4244 Hyperkalemia and worsening renal function are a concern, especially in patients with underlying
chronic kidney disease. In the Randomized Aldactone Evaluation Study (RALES), which demonstrated a 30% reduction
in death in patients with NYHA III or IV heart failure and
an EF of 35% or less, with an average dose of 26 mg of
spironolactone daily, the mean increase in creatinine was
0.1 mg/dL and the mean increase in potassium was
0.3 mmol/L.42 No significant difference in the rate of hyperkalemia was noted between the treatment and control
groups. Following the publication of the RALES in 1999, a
claims data analysis in patients over 65 years of age from
Ontario, Canada, revealed significantly increased rates of hospital admission for hyperkalemia and hyperkalemic death in
patients with heart failure taking spironolactone in addition
to an ACE inhibitor.45 This argues for close monitoring of
potassium levels in patients receiving aldosterone antagonists in addition to ACE inhibitors, especially in the setting
of baseline renal dysfunction.

Neurohormonal escape is a phenomenon observed in

patients treated with long-term ACE inhibitors in which circulating levels of angiotensin II eventually return to pretreatment levels. Angiotensin II receptor blockers (ARBs) blunt
the effects of this phenomenon by binding competitively to
the AT1 receptor. A large meta-analysis of 24 randomized
trials showed the superiority of ARBs to placebo in patients
with intolerable adverse effects with ACE inhibitors and
their noninferiority in all-cause mortality or hospitalizations
when compared with ACE inhibitors. In addition, the randomized Valsartan in Acute Myocardial Infarction Trial
(VALIANT) found the ARB valsartan to be noninferior to
the ACE inhibitor captopril with regard to all-cause mortality.46 In this trial, the combination of valsartan and captopril
in patients with left ventricular dysfunction or heart failure
following MI who were receiving background beta-blocker
therapy was associated with an increase in adverse events
without any added benefit compared with monotherapy for
either group.46 This finding was supported by previous data
from Valsartan Heart Failure Trial (Val-HeFT), which suggested that the addition of valsartan in patients already
receiving treatment with ACE inhibitors and beta blockers
was associated with a trend toward worse outcomes.47 Thus,
the initial clinical strategy should be to use a two-drug
combination first (ACE inhibitor and beta blocker; if ACE
inhibitor intolerant, ARB and beta blocker). In symptomatic
patients (NYHA class II to IV), an aldosterone antagonist
should be strongly considered, but a four-drug regimen
combining all of the above classes of medications should be
avoided.
The relatively recent Aliskiren Trial on Acute Heart Failure
Outcomes (ASTRONAUT) tested a direct renin inhibitor,
aliskerin, in addition to other neurohormonal antagonists, in
patients within a week postdischarge from a hospitalization

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heart failure 8

Table 3 Drugs and Devices with a Demonstrated Survival Benefit in Heart Failure
with a Reduced Ejection Fraction
Drug or Device

Trial

Year
Published

Inclusion Criteria

Sample
Size

Average
Follow-up
Duration (mo)

Number Needed to
Treat to Prevent
One Death

ACE inhibitors
Enalapril

CONSENSUS

1987

NYHA IV, dilated left

ventricle on diuretics
and digoxin

253

5.6

Enalapril

SOLVD

1991

Symptomatic HF and
EF 35%

2,569

41

22.2

Captopril

SAVE

1992

Asymptomatic post-MI,
EF 40%

2,231

42

20

Candesartan*

CHARMAlternative

2003

NYHA IIIV, EF 40%,

intolerant to ACE
inhibitor

2,028

34

33

Valsartan

VALIANT

2003

Post-MI, symptomatic
HF, and EF 35%

14,703

25

N/A

Spironolactone

RALES

1999

NYHA IIIIV, EF 35%

1,663

24

Spironolactone

EPHESUS

2003

Post-MI and symptomatic HF, EF 40%

6,642

16

44

Eplerenone

EMPHASIS

2010

NYHA II, EF 30%

2,737

21

37

Carvedilol

U.S. Carvedilol

1996

Symptomatic HF and
EF 35%

1,094

22

Carvedilol

COPERNICUS

2001

Severe symptomatic
HF (dyspnea at rest
or minimal exertion),
EF < 25%

1,959

10

18

Bisoprolol

CIBIS-II

1999

NYHA IIIIV, EF 35%

2,647

16

18

Metoprolol succinate

MERIT-HF

1999

NYHA IIIV, EF 40%

3,991

12

26

A-HeFT

2004

African American,
NYHA III or IV,
EF < 45%

1,050

10

25

Sacubitril/valsartan

PARADIGM-HF

2014

NYHA IIIV, EF 40%

8,442

27

36

ICD

MADIT

1996

NYHA IIII, previous

MI, EF 35%, NSVT

196

27

MADIT-II

2002

NYHA IIII, MI more

than 30 days
previously, EF 30%

1,232

20

18

SCD-HeFT

2005

NYHA IIIII, EF 35%,

ischemic or
nonischemic

2,521

45

14

CARE-HF

2005

NYHA IIIIV, EF
35%, QRS > 120 ms

813

29

10

Angiotensin receptor blockers

Aldosterone antagonists

Beta blockers

Vasodilator
Hydralazine/isosorbide
dinitrate
Neprilysin inhibitor

CRT

ACE = angiotensin-converting enzyme; A-HeFT = African-American Heart Failure Trial; CARE-HF = Cardiac Resynchronization in Heart Failure; CHARM = Candesartan in Heart
Failure Assessment of Reduction in Mortality and Morbidity; CIBIS = Cardiac Insufficiency Bisoprolol Study; CONSENSUS = Cooperative North Scandinavian Enalapril Survival
Study; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; CRT = cardiac resynchronization therapy; EF = ejection fraction; EMPHASIS = Eplerenone in
Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS = Eplerenone PostAcute Myocardial Infarction Heart Failure Efficacy and Survival Study; HF =
heart failure; ICD = implantable cardioverter-defibrillator; MADIT = Multicenter Automatic Defibrillator Implantation Trial; MERIT = Metoprolol CR/XL Randomised Intervention
Trial; MI = myocardial infarction; NYHA = New York Heart Association; PARADIGM-HF = Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with ACE
Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; RALES = Randomized Aldactone Evaluation Study; SAVE = Survival and Ventricular Enlargement; SCD-HeFT = Sudden Cardiac Death in Heart Failure Trial; SOLVD = Studies of Left Ventricular Dysfunction; VALIANT = Valsartan in Acute Myocardial Infarction Trial.
*All-cause mortality was not a primary or prespecified secondary outcome; achieved borderline significance (p = .11) until adjustment for covariates (p = .03).

VALIANT compared valsartan with captopril with a combination of both. Harm was associated with the combination. Valsartan was noninferior to captopril with regard
to all-cause mortality.

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heart failure 9

Table 4 Neurohormonal Antagonist Dosing in Heart Failure with a Reduced Ejection Fraction
Drug

Starting Dose

Maximum Dose

Dose Achieved in Clinical Trials

(total daily dose)

Angiotensin-converting enzyme
inhibitors
Captopril

6.25 mg t.i.d

50 mg t.i.d

123 mg

Enalapril

2.5 mg b.i.d

10 mg b.i.d

1118 mg

Lisinopril

2.55 mg daily

40 mg daily

33 mg

Ramipril

1.252.5 mg daily

10 mg daily

Fosinopril

510 mg daily

40 mg daily

Quinapril

510 mg b.i.d

40 mg b.i.d

Trandolapril

0.5 mg daily

4 mg daily

Valsartan

40 mg b.i.d

160 mg b.i.d

254 mg

Candesartan

48 mg daily

32 mg daily

23 mg

Losartan

25 mg daily

150 mg daily

129 mg

Bisoprolol

1.25 mg daily

10 mg daily

8.6 mg

Carvedilol

3.125 mg b.i.d

25 mg b.i.d (50 mg b.i.d

if weight > 85 kg)

3745 mg

Metoprolol succinate

25 mg daily

200 mg daily

159 mg

Spironolactone

12.525 mg daily

2550 mg daily

26 mg

Eplerenone

25 mg daily

50 mg daily

3943 mg

37.5 mg/20 mg t.i.d

75 mg/40 mg t.i.d

142 mg/76 mg

50 mg b.i.d

200 mg b.i.d

375 mg

Angiotensin receptor blockers

Beta blockers

Aldosterone antagonists

Vasodilators
Hydralazine-isosorbide dinitrate
Combination neprilysin inhibitor/
angiotensin receptor blocker
Sacubitril/valsartan

for decompensated heart failure with an EF of 40% or less.48

No significant difference in cardiovascular death or hospitalization at 6 or 12 months was noted. Although aliskerin
was associated with a reduction in circulating natriuretic
peptides, any disease-modifying effect was overcome by
excessive adverse events, including hypotension, renal dysfunction, and hyperkalemia.
The combination of hydralazine and long-acting nitrates
has been demonstrated to improve survival in patients with
symptomatic heart failure and an EF of less than 45%. Hydralazine decreases intracellular calcium in vascular smooth
muscle cells, thereby reducing systemic vascular resistance;
nitrates are transformed in smooth muscle cells into nitric
oxide, which stimulates cyclic guanosine monophosphate
production and consequent venous and arterial vasodilation. This combination improves survival, but not to the
magnitude demonstrated by ACE inhibitors or ARBs.49 In
individuals with HFrEF who are unable to tolerate reninangiotensin-aldosteronebased therapy for reasons such as
renal insufficiency or hyperkalemia, this combination is
preferred as a disease-modifying approach. Based on a promising subgroup analysis of the Vasodilator-Heart Failure
Trial (V-HeFT), a randomized controlled trial including only

African Americans studied a fixed-dose isosorbide dinitrate/

hydralazine combination in patients with HFrEF (NYHA
class III or IV, EF 45%) who were receiving standard background therapy.50 The study demonstrated benefit in overall
survival and heart failure hospitalization in the treatment
group. Adherence to this regimen is limited by the three
times per day dosing schedule.
Ivabradine, an inhibitor of the If current in the sinoatrial
node, slows the heart rate without a negative inotropic
effect. The Systolic Heart Failure Treatment with Ivabradine
Compared with Placebo Trial (SHIFT) was conducted in
patients with NYHA class II or III HFrEF (EF 35%), a heart
rate over 70 beats per minute, and a history of hospitalization for heart failure during the previous 12 months.51
Ivabradine reduced the combined end point of cardiovascular death or heart failure hospitalization by 18%; this was
mainly driven by a reduction in heart failure hospitalization.
This study population was not necessarily representative of
a North American patient with HFrEF because most did not
receive an implantable cardioverter-defibrillator (ICD) or
CRT. Only 60% were on mineralocorticoid receptor antagonists, and although 90% received beta blockers, only a quarter
were on target doses. Whether this agent would have been

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effective in patients receiving robust, guideline-recommended
therapy for heart failure remains unclear. Although not
included in the American Heart Association/American College
of Cardiology heart failure guidelines from 2013, the 2012
European Society of Cardiology guidelines for the treatment
of heart failure suggest ivabradine as second-line therapy
(prior to consideration of digoxin) in patients with a resting
heart rate greater than 70 beats per minute and ongoing
symptoms despite guideline-based therapy with ACE inhibitors, beta blockers, and mineralocorticoid receptor antagonists.52 Another group of patients in whom potential benefit
may be expected includes those unable to tolerate beta
blockers.
Most recently, inhibition of neprilysin (an endopeptidase
that degrades natriuretic peptides, bradykinin, and adrenomedullin) in combination with the ARB valsartan demonstrated superiority to the ACE inhibitor enalapril.53 The
Prospective Comparison of Angiotensin Receptor-Neprilysin
Inhibitor with ACE inhibitor to Determine Impact on Global
Mortality and Morbidity in Heart Failure (PARADIGM-HF)
trial randomized 8,442 patients with symptomatic (NYHA
class II to IV) heart failure and an EF of 40% or less to the
combination neprilysin inhibitorARB (sacubitril/valsartan)
at a dose of 200 mg twice daily versus enalapril at a dose of
10 mg twice daily. The trial demonstrated a 16% reduction
in death from any cause (2.8% absolute risk reduction) over
a median follow-up of 27 months; in addition, there was a
21% reduction in heart failure hospitalizations and a decrease
in symptoms related to heart failure, with slightly higher
rates of symptomatic hypotension. It should be noted that
the use of BNP assays becomes inaccurate in the setting of
these drugs, whereas NT-proBNP assays may still remain
accurate.
Digitalis glycosides (i.e., digoxin) exert a mild inotropic
effect, attenuate carotid sinus baroreceptor activity, and are
sympathoinhibitory. These effects decrease serum norepinephrine levels, plasma renin levels, and possibly aldosterone levels. The Digitalis Investigation Group (DIG) trial
demonstrated a reduction in heart failure hospitalizations in
the treatment group but no reduction in mortality or
improvement in quality of life.54 Importantly, treatment with
digoxin resulted in a higher mortality in women than in
men, whereas the benefit is attenuated in women. It should
be noted that low doses of digoxin are sufficient to achieve
any potential benefit, and higher doses may breach the
therapeutic safety index. Trough digoxin levels should be
checked to minimize toxicity, especially in those with baseline
renal dysfunction, and although dose reductions are indicated for higher levels ( 0.9 ng/mL), no adjustment is required
for low levels. Generally, digoxin is relegated to therapy
employed in those who remain profoundly symptomatic
despite optimal neurohormonal blockade (or those intolerant of neurohormonal antagonists) and adequate volume
control.
Loop diuretic agents are often required in HFrEF. Over
time, there is often variability in the dose required given
changes in absorption, renal function, sodium and water
homeostasis, and the degree of neurohormonal activation.
Importantly, clinical trial data confirming efficacy are limited,
and no data suggest that chronic diuretic administration
improves survival. Thus, diuretic agents should ideally be
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heart failure 10
used in tailored dosing schedules to avoid excessive exposure. Indeed, diuretics are essential initially to achieve volume control prior to initiation and titration of neurohormonal
antagonists.
HFrEF is accompanied by a hypercoagulable state and
therefore an increased risk of thromboembolic events, including stroke, systemic embolism, and pulmonary embolism.
Although long-term oral anticoagulation is established in
certain groups, such as those with atrial fibrillation, the data
are insufficient to support the use of warfarin in patients in
normal sinus rhythm without a history of thromboembolic
events or echocardiographic evidence of left ventricular thrombus. The largest warfarin trial, Warfarin versus Aspirin in
Reduced Cardiac Ejection Fraction (WARCEF), randomized
2,305 patients with an EF of 35% or less (mean EF 25%) in
sinus rhythm to either full-dose aspirin or warfarin with an
international normalized ratio (INR) target of 2 to 3. After a
median follow-up of 3.5 years, there was a slight reduction
in ischemic stroke in the warfarin group, which was offset
by an increase in major and intracranial bleeding; there was
no difference in mortality or in the combined primary end
point. Current guidelines support the use of aspirin in
patients with ischemic cardiomyopathy but do not recommend warfarin unless there is a coexisting indication.
ICDs in Heart Failure with a Reduced Ejection Fraction
Sudden death due to ventricular arrhythmias is the mode
of death in approximately half of patients with heart failure
and is proportionally prevalent in those HFrEF patients with
early stages of the disease. Patients who experience near-fatal
ventricular fibrillation or sustained ventricular tachycardia
are considered to be at very high risk and qualify for placement of an ICD as secondary prevention.55 Although assigning risk and selecting patients for primary prevention ICD
implantation are challenging, the degree of residual left
ventricular dysfunction despite optimal medical therapy
(EF 35%) and the underlying etiology (post-MI or ischemic
cardiomyopathy) are the two most potent risk factors for
sudden death. At this time, patients with NYHA IIIII symptoms of heart failure and an EF of 35% or less, irrespective
of the etiology of heart failure, are appropriate candidates
for ICD implantation.56 In patients with a previous MI and
optimal medical therapy with a residual EF of 30% or less
(even if asymptomatic), placement of an ICD is appropriate.57
In patients with a terminal illness and a predicted survival
of less than 6 months or in those with NYHA class IV symptoms
that are refractory to medications and are not candidates for
cardiac transplantation, the discomfort of multiple ICD
shocks must be carefully weighed against the potential survival benefits. If a patient meets the electrocardiographic
criteria for CRT, combined CRT with an ICD (CRT-D) is
often employed.
crt in heart failure with a reduced ejection
fraction
Asynchronous contraction between the interventricular septum and the lateral wall of the left ventricle related to electrical
conduction system disease impairs systolic function, decreases
the efficiency of mechanical contraction, and adversely affects
ventricular filling. This asynchronous contraction is particularly

cardio
prominent in the presence of a left bundle branch block. With
placement of a pacing lead via the coronary sinus into an epicardial vein overlying the lateral wall of the left ventricle,
CRT enables synchronous ventricular contraction by aligning
the timing of activation of the lateral wall with the interventricular septum. Early studies showed improved exercise
capacity, a reduction in symptoms, and evidence of reverse
remodeling. The Cardiac Resynchronization in Heart Failure
(CARE-HF) trial was the first study to demonstrate a reduction in all-cause mortality with CRT placement in patients
with an EF of 35% or less with continued severe heart failure
symptoms (NYHA class III or IV) despite optimal medical
therapy.58 More recent clinical trials have demonstrated
disease-modifying properties of CRT in combination with
a defibrillator compared with a defibrillator alone even
in minimally symptomatic patients with HFrEF. The
Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) enrolled 1,798 patients with an EF of 30% or
less and a QRS duration of 120 ms or greater (80% were
NYHA class II),59 whereas the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization
Therapy (MADIT-CRT) trial enrolled 1,820 patients with an
EF of 30% or less and a QRS duration of 130 ms or greater
(85% were NYHA class II).60 Both trials demonstrated reductions in the occurrence of a combined end point of death and
heart failure events. Patients without symptoms of heart failure (NYHA class I) are underrepresented in all CRT trials. Only
MADIT-CRT (15% NYHA class I) and Resynchronization
Reverses Remodeling in Systolic Left Ventricular Dysfunction
(REVERSE) (17.5% NYHA class I) included asymptomatic
patients. The REVERSE trial randomized 419 patients to
CRT-on versus CRT-off in a 2:1 fashion and demonstrated a
favorable remodeling benefit with CRT-on using a surrogate
end point of end-systolic volume index, which was evident in
both NYHA class I and II patients. The most benefit in the
mildly symptomatic HFrEF patient accrues by applying this
therapy in those with a QRS duration of 150 ms or greater and
a left bundle branch block. Attempts to further optimize
patient selection and expand indications for CRT using modalities
other than electrocardiography have proven disappointing. In
particular, echocardiographic measures of dyssynchrony vary
tremendously, and narrow QRS dyssynchrony has not proven
to be a good target for treatment.61 Uncertainty surrounds the
influence of CRT in those with ADHF, a predominant right
bundle branch block pattern, atrial fibrillation, and evidence
of scar in the lateral wall, which is the precise location
where the left ventricular lead is positioned.
revascularization in heart failure with
a reduced ejection fraction
Coronary artery bypass grafting (CABG) is considered in
patients with ischemic cardiomyopathy with multivessel
coronary artery disease. The recognition that hibernating
myocardium, defined as myocardial tissue with abnormal
mechanical function but maintained cellular function, could
recover after revascularization led to the notion that revascularization with CABG would be useful in those with viable
myocardium. Revascularization is most supported in individuals with angina and left ventricular failure. Revascularization in those with left ventricular systolic dysfunction in
the absence of angina remains controversial. The Surgical

heart failure 11
Treatment for Ischemic Heart Failure (STICH) trial enrolled
1,212 patients with an ejection fraction of 35% or less and
coronary artery disease amenable to CABG and randomly
assigned them to medical therapy alone or medical therapy
plus CABG. There was no significant difference between
groups with respect to the primary end point of death from
any cause in an intention-to-treat analysis. When analyzed
using a per-protocol or as-treated analysis to account for significant crossover, death from any cause was lower in those
undergoing CABG.62 The study has been criticized for the
low rate of enrolment per center, which may have been due
to a lack of equipoise at the time. The notion of revascularization in patients with coronary disease and left ventricular
systolic dysfunction was already an accepted treatment
strategy and was supported by the guidelines. In addition,
patients with left main coronary artery stenosis greater than
50% were excluded from the trial. The STICH trial examined
only surgical revascularization and did not address the potential for percutaneous revascularization in those patients in
whom the coronary anatomy may be suitable. An ancillary
study of this trial examining about half of the patients
included in the overall study who underwent myocardial
viability testing (using thalium single-photon emission
computed tomography or dobutamine echocardiography)
determined that the detection of hibernating myocardium
prerevascularization did not materially influence the efficacy
of this approach, nor did it help define a population unlikely
to benefit if hibernation was not detected.63
mitral valve surgery in heart failure with
a reduced ejection fraction
Mitral regurgitation (MR) develops in varying degrees in
patients with HFrEF and a dilated left ventricle and is associated with a poor prognosis. Ventricular dilation and apical
displacement of the subvalvular mitral apparatus, annular
dilatation, and leaflet noncoaptation in the setting of anatomically normal papillary muscles, chordal structures, and
valve leaflets characterize such functional MR. In patients
who are not candidates for surgical coronary revascularization, mitral valve repair remains controversial. Ischemic MR
(or infarct-related MR) is typically associated with leaflet
tethering and displacement related to abnormal left ventricular wall motion and geometry. Even though correction of
MR may be technically feasible, no evidence to support the
use of surgical or percutaneous valve correction for functional MR exists as disease-modifying therapy.
management of atrial fibrillation in heart
failure with a reduced ejection fraction
Atrial fibrillation is commonly associated with HFrEF and
is associated with a worse overall prognosis. Clinical trials
with patients with both HFrEF and atrial fibrillation have
not demonstrated any particular advantage to a rhythm control strategy either with antiarrhythmic drugs or pulmonary
vein isolation (catheter ablation of atrial fibrillation).64,65
A patient-centered approach should be pursued, and a
rhythm control strategy should be adopted in patients with
clear symptomatic decompensation in the setting of atrial
fibrillation or those who prove difficult to rate control. Control
of the ventricular rate is often achieved with the use of beta
blockers and digoxin; nondihydropyridine calcium channel
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heart failure 12

blockers such as diltiazem and verapamil should be avoided

given the negative inotropic effects and potential for harm.66
For patients in whom rate or rhythm control is not achievable, ablation of the atrioventricular node and implementation of CRT is an option.
Management of Heart Failure with a Preserved
Ejection Fraction
Unlike the disease-modifying therapies that have proven
survival benefit in HFrEF, no trial to date has demonstrated
a survival benefit or any meaningful functional or symptomatic end point in HFpEF. HFpEF is a heterogeneous group
of disorders, and in certain conditions (such as heart failure
with associated valvular disease, constrictive pericarditis,
amyloidosis, hemochromatosis, Fabry disease), there are
specific treatments. The complexity and heterogeneity of
this mixed bag of diagnostic entities are the principal cause
of the lack of cohesive therapeutic strategies [see Figure 2]. At
the current time, the overall management of HFpEF should
focus on volume management with diuretics and blood pressure control in the hypertensive patient. In addition, special
attention should be paid to the structural and functional
abnormalities noted on noninvasive testing as well as ancillary testing abnormalities, which may suggest a specific disease entity that requires specific treatment. For example,
distinguishing constrictive pericarditis from HFpEF is
important given the potential for a surgical cure in constrictive pericarditis. Diagnosis of light chain (AL, primary)
amyloidosis early in the disease course is imperative as the
disease is often aggressive, and chemotherapy with or without
stem cell transplantation may significantly improve survival.
Trials attempting to identify disease-modifying therapy in
HFpEF have been disappointing; in particular, trials investigating agents that antagonize the renin-angiotensin-aldosterone

system have been uniformly negative [see Table 5].6769 The

RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical
Status and Exercise Capacity in Heart Failure with a Preserved Ejection Fraction) trial randomized 216 patients to
sildenafil (initially 20 mg three times daily, titrated to 60 mg
three times daily) versus placebo.70 Following 24 weeks of
therapy, there was no difference in symptoms or functional
capacity as measured by the 6-minute walk test and cardiopulmonary exercise testing. The recently published Treatment of Preserved Cardiac Function Heart Failure with an
Aldosterone Antagonist (TOPCAT) trial randomized 3,445
patients with an EF of 45% or greater to either spironolactone
(mean daily dose 25 mg) or placebo.71 There was no difference in the composite primary outcome of death, aborted
cardiac arrest, or hospitalization for heart failure, but there
was twice the rate of hyperkalemia (19% versus 9% in the
treatment and control groups, respectively). An interesting
post hoc analysis revealed the benefit of spironolactone
when patients from the countries of Russia and Georgia
were excluded. Patients in these countries were more likely
to be enrolled on the basis of a heart failure hospitalization
in the previous 12 months rather than a BNP elevation and
experienced a lower event rate, possibly suggesting a less
sick population or patients with an alternate diagnosis at
enrolment rather than heart failure. Although intriguing,
based on the overall trial results, spironolactone cannot be
recommended for routine management of chronic HFpEF.
Long-acting nitrates are commonly prescribed for symptoms related to HFpEF based on a hypothetical benefit with
regard to vasodilation and potential for treatment of symptoms related to coexisting coronary artery disease and pulmonary hypertension. The recently published Nitrates
Effect on Activity Tolerance in Heart Failure with Preserved
Ejection Fraction (NEAT-HFpEF) trial randomized 110 patients
to isosorbide mononitrate (dose titrated to 120 mg daily)

Loss of compliance
Impaired relaxation
Hypertrophy
Fibrosis/altered collagen
Apoptosis
Infarction/Ischemia
Cellular dysfunction

Heart

Loss of compliance
Altered elastin and collagen
Calcification
Atherosclerosis
Endothelial dysfunction

Hypertension
Aging
Atherosclerosis
Diabetes

Blood
Vessels

Kidney
Worsening Renal Function
Figure 2 The complex pathophysiology and principal aberrations underlying heart failure with preserved ejection fraction (HFpEF).
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heart failure 13

Table 5 Randomized, Placebo-Controlled Trials in Heart Failure with a Preserved Ejection Fraction

Therapy

Trial

Year
Published

Sample
Size

Average
Followup

Outcome
in
Treatment
Group

Outcome
in
Control
Group

p
Value

Symptomatic HF, EF Death from CV

> 40%
cause or HF hospitalization

37 mo

22%

24%

NS

Symptomatic HF
with an EF > 45%
and abnormal
diastolic parameters on echocardiography

6 mo

51%

40%

NS

Any EF, age 70 yr, Death from any

cause,
symptomatic
hospitalization
HF (35% had EF >
for CV cause
35%, few with
EF > 50%)

21 mo

31%

35%

.04

Inclusion Criteria

Primary Outcome

Candesartan

CHARMpreserved

2003

3,023

Carvedilol

SWEDIC

2004

113

Nebivolol

SENIORS

2005

2,128

Perindopril

PEP-CHF

2006

850

Symptomatic HF,
EF > 40%,
age; 70 yr

Death from any

cause or HF hospitalization

25 mo

24%

25%

NS

Digoxin

DIG (HFpEF
substudy)

2006

988

Symptomatic HF,
sinus rhythm,
EF; > 45%

HF mortality or HF
hospitalization

37 mo

21%

24%

NS

Irbesartan

I-PRESERVE

2008

4,128

Symptomatic HF,
EF 45%

Death from any

cause, hospitalization for CV cause

50 mo

36%

37%

NS

Sildenafil

RELAX

2013

216

EF > 50% and

elevated BNP or
pulmonary
arterial wedge
pressure

Aerobic capacity
(change in
peak oxygen
consumption)

6 mo

2%

2%

NS

Spironolactone TOPCAT

2014

3,445

Symptomatic HF
(with hospitalization in previous
year or BNP
elevation) and
EF 45%

Death from CV
cause, aborted
cardiac arrest, or
HF hospitalization

40 mo

19%

20%

NS

Isosorbide
NEATmononitrate
HFpEF

2015

110

Symptomatic HF,
EF 50%,
age 50 yr

Daily activity level

(using patientworn accelerometer, average daily
accelerometer
units)

6 wk

8,922 units

9,303
units

NS

Improvement in
composite of
echocardiographybased diastolic
function
parameters

BNP = brain natriuretic peptide; CHARM = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; CV = cardiovascular; DIG = Digitalis Investigation
Group; EF = ejection fraction; HF = heart failure; HFpEF = heart failure with a preserved ejection fraction; I-PRESERVE = Irbesartan in Patients with Heart Failure and Preserved
Ejection Fraction; NEAT-HFpEF = Nitrates Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction; NS = not significant; PEP-CHF = Perindopril in Elderly
People with Chronic Heart Failure; RELAX = Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with a Preserved Ejection Fraction;
SENIORS = Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure; SWEDIC = Swedish Doppler-Echocardiographic Study;
TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.

versus placebo for 6 weeks, with subsequent crossover and

follow-up for an additional 6 weeks.72 Patients wore accelerometers to measure activity level. While treated with nitrates,
patients had a trend toward a lower level of activity and
were active for 30 minutes less per day than while on placebo
(p = .02), suggesting no role for nitrates in the management
of symptomatic HFpEF.
Advanced Heart Failure
recognizing advanced heart failure
The most recent heart failure guidelines proposed by the
American Heart Association in 2013 place particular importance

on categorizing patients into a particular stage [see Table 6].73

The time course and path of progression from stage A (at
risk for heart failure) to stage D (advanced heart failure)
are variable. Some patients may first present at an advanced
stage having progressed subclinically for years previously,
whereas others may remain at earlier stages indefinitely.
Identifying a patient with stage D, or advanced, heart failure
is often difficult and requires the integration of clinical, biochemical, imaging, exercise, and hemodynamic data.74 Yet
identification of patients with stage D heart failure is
extremely important as there is a meaningful difference in
the prognosis and response to therapy. Neurohormonal
antagonists may be less well tolerated in this population and

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heart failure 14

Table 6 Categorization of Heart Failure according to AHA/ACC Heart Failure Stage,

NYHA Functional Class, and INTERMACS Level
AHA/ACC Heart Failure Stage

NYHA Functional Class

INTERMACS Level

At high risk for heart failure

Structural heart disease but no signs

or symptoms of heart failure

No symptoms with usual activity

Previous or current symptoms of

heart failure

II

Symptoms with usual activity

III

Symptoms with less than usual

activity

Advanced NYHA class 3

Exertionlimited

Symptoms at rest or with

minimal activity

Exertionintolerant

Resting symptoms

Stable but inotrope dependent

Progressive decline despite inotropes

Critical cardiogenic shock

Refractory heart failure requiring

specialized interventions

IV

ACC = American College of Cardiology; AHA = American Heart Association; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support;
NYHA = New York Heart Association.

may even be contraindicated in those who rely heavily on

the compensatory mechanisms of neurohormonal activation
to maintain an adequate cardiac output and blood pressure.
Given the poor prognosis in stage D heart failure and the
limitations to medical therapy in this cohort, strong consideration should be given to MCS or cardiac transplantation,
which may improve long-term survival and quality of life.
The use of cardiac transplantation in therapy is covered elsewhere in this publication. In general, once classic evidencebased therapy is exhausted and the heart failure state
continues to progress relentlessly, therapeutic targets shift
from the neurohormonal model to surgical options that
exploit the myocardial stress-and-strain relationship. Thus,
a variety of treatment targets are being investigated that
invoke Laplaces law (stress-and-strain relationship in a
cavity is directly related to the diameter and intracavitary
pressure and inversely to its wall thickness) [see Figure 3].
selecting patients for a durable left
ventricular assist device
Certain patients may benefit from MCS either as a bridge
to cardiac transplantation, as lifetime (destination) therapy,
or as a bridge to decision in which the ultimate decision
of transplant candidacy is deferred to allow for a better
understanding of the patient and his or her comorbidities
following MCS implantation. This designation is somewhat
arbitrary, and up to a third of patients initially designated as
transplant candidates will no longer be so following MCS,
whereas a quarter of patients initially designated for destination therapy will ultimately go on to transplantation.
In the early 1990s, large left ventricular assist devices
(LVADs) that produced pulsatile flow were initially used for
left ventricular support in patients awaiting cardiac transplantation. This strategy was borne out of necessity given
long waiting times for cardiac transplantation and was not
based on randomized data. Equipoise in decision making for
LVAD support in patients who were not transplant candidates led to the Randomized Evaluation of Mechanical
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Assistance for the Treatment of Congestive Heart Failure

(REMATCH) trial.75 One hundred twenty-nine nontransplant candidates with end-stage heart failure were randomized to continued medical therapy (72% of patients
supported with continuous intravenous inotropes) versus
an LVAD. This trial demonstrated a dramatic survival
advantage at 1 year (53% survival in the LVAD group and
25% survival in the medical therapy group) and supported
the concept of lifetime or destination therapy using MCS
systems. The initial adoption of pulsatile devices was low
given limited device durability and frequent morbidity;
however, the advent of smaller and more reliable continuousflow devices led to a significant increase in the use of durable LVADs over the past decade. In 2013, the number of
durable MCS devices in the United States (N = 2,642; 97%
continuous-flow LVADs, 44% for destination therapy)
exceeded the number of cardiac transplantations performed.76,77 For the past decade, the number of annual cardiac transplantations worldwide (mostly performed in the
United States and Europe) has remained relatively fixed at
around 4,000 due to inabilities to expand the donor pool.
Improving clinical outcomes and experience with currentgeneration LVADs have contributed to a growing population of transplantation-ineligible patients supported with
these devices as destination therapy. Inevitably, technological advances will allow MCS to be applied to less sick
patients, and appropriate patient selection will be paramount in prolonging and improving life while achieving
cost-effectiveness.78
Determining candidacy for MCS or cardiac transplantation requires the identification of a patient with a poor prognosis if treated with medical therapy alone. This assessment
relies heavily on the degree of symptoms, refractoriness to
traditional disease-modifying therapy, and the presence of
an unfavorable hemodynamic profile. The NYHA classification system alone is insufficient to provide an adequate
prognostic assessment. Therefore, to add more granularity
in the classification of those with severe symptoms, the

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heart failure 15

Figure 3 Concepts underlying surgical therapy in advanced heart failure using Laplaces law. CRT = cardiac resynchronization therapy.
Interagency Registry for Mechanically Assisted C
irculatory
Support (INTERMACS) system (which assigns a level 1
through 7 to patients based on the degree of illness) has been
developed to further refine overall disease severity in patients
with advanced heart failure [see Table 6]. At the current time,
most patients referred for LVAD implantation are either categorized as INTERMACS level 1 (critical cardiogenic shock),
level 2 (progressive decline on inotropic therapy), or level 3
(stable but inotropic therapy dependent).76 INTERMACS
level 1 patients pose a particular challenge to LVAD implantation with an increased rate of perioperative mortality (relative risk 1.55).79 This increased risk is at least in part related to
the end-organ dysfunction associated with cardiogenic shock
and the inflammatory state of severe shock, leading to
increased postimplantation bleeding, infection, and multisystem organ failure. In response to the realization of the perioperative risk in patients with cardiogenic shock, the proportion
of patients undergoing durable MCS implantation at INTERMACS level 1 has decreased over the past decade.76,79,80 Avoidance of support in these patients is not an adequate strategy,

and the management likely should include an attempt to

provide immediate stability with temporary MCS devices
such as intra-aortic balloon counterpulsation, percutaneous
or surgical centrifugal devices, percutaneous axial flow
devices, or venoarterial extracorporeal membrane oxygenation in an effort to restore end-organ perfusion and potentially reduce the perioperative risk of durable LVAD
implantation.81 In general, patients with cardiogenic shock
who can be stabilized with percutaneous support may be
candidates for a durable LVAD, whereas patients who
demonstrate refractory shock or experience reversible
end-organ dysfunction (i.e., renal, hepatic, or neurologic)
despite temporary MCS are likely suboptimal candidates for
LVAD implantation.
Patients dependent on inotropic therapy (INTERMACS
levels 2 and 3) currently represent nearly two thirds of
patients undergoing LVAD implantation and likely also represent the most appropriate use of the current technology.
Patients treated with inotropic therapy due to refractory
end-organ hypoperfusion or refractory symptoms related to

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advanced heart failure have a very poor prognosis with
medical therapy alone. Of the 61 patients in the medical
therapy arm of the REMATCH trial, 72% of patients were on
continuous inotropic infusion, and by 1 year, only 25% of
medically treated patients were alive, which decreased to
8% by 2 years.75 Two other small prospective analyses have
demonstrated an even more dismal 1-year survival of 6 to
11% of patients dependent on inotropic support.82,83 In contrast, the expected 1-year survival of patients following
implantation of a continuous-flow LVAD now approaches
80%.79 Although the patient populations in the inotropic
support trials differ from those undergoing LVAD implantation enrolled in the INTERMACS registry, these data
suggest a dramatic survival advantage favoring durable

MCS in INTERMACS level 2 and 3 patients.

Patients in INTERMACS levels 4 through 7 suffer from
advanced heart failure but are not inotrope dependent; these
patients are more challenging to identify. Currently, only
18.5% of patients who undergo durable MCS are levels 4
through 7 (mostly INTERMACS level 4).79 The Medical Arm
of the Interagency Registry for Mechanically Assisted Circulatory Support (MEDAMACS) is an ongoing registry
coupled to the INTERMACS registry that aims to further
characterize medically managed patients in INTERMACS
levels 4 to 7.84 The pilot data from the first 166 patients
enrolled in MEDAMACS demonstrate a 1-year survival of
78% in INTERMACS level 6/7, 67% in INTERMACS level 5,
and 39% in INTERMACS level 4. Based on these limited
data, there is unlikely to be a significant survival advantage
to LVAD implantation in INTERMACS level 6 or 7, and
these patients are likely too well to benefit from durable
MCS implantation.
INTERMACS level 4 patients are beginning to gain
acceptance as an appropriate candidate group. Patients in
this subgroup exhibit symptoms of dyspnea and fatigue on
minimal activity, are usually house bound due to the severity of symptoms, and experience a poor quality of life and
an excess 1-year mortality. The overall prognosis in patients
categorized as INTERMACS level 4 is not as clear as those
requiring inotropes or in shock and likely has a greater
variability; therefore, further estimation of prognosis in
these patients is warranted with the use of other prognostic
indicators in chronic heart failure [see Table 7].74,8591 INTERMACS levels 4 to 6 patients were analyzed prospectively in
the recently reported prospective observational Risk Assessment and Comparative Effectiveness of Left Ventricular
Assist Device [LVAD] and Medical Management (ROADMAP) trial, which offered all enrolled patients implantation of a continuous-flow LVAD and compared those who
underwent implantation with those who chose medical
therapy.92 Of the 196 patients enrolled, 95 underwent
implantation of an LVAD. By intention to treat, although
there was no difference in mortality (because patients
with worsening clinical status despite medical therapy
would transition to LVAD implantation), there were notable improvements in functional capacity, quality of life,
and depression in the LVAD group. The potential symptomatic and survival benefits in INTERMACS level 4
patients must be carefully balanced with the risks of
LVAD therapy (e.g., stroke, LVAD thrombosis, bleeding,
and infection).
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heart failure 16

Table 7 Poor Prognostic Indicators in

Heart Failure
Clinical history, signs, and symptoms
Repeated heart failure hospital admissions ( 2 in 1 yr)
Dyspnea at rest (NYHA class IV) or with minimal exertion
Tachycardia (heart rate > 100 beats/min) and/or hypotension
Cardiac cachexia
Pharmacologic and device considerations
High diuretic requirement (furosemide equivalent > 160 mg/day)
Inability to tolerate neurohormonal antagonists (due to
hypotension or renal dysfunction)
Current or previous need for inotropic support
Nonresponder to CRT
Repeated ICD shocks
Biochemical abnormalities
Anemia
Hyponatremia (sodium < 135 mmol/L)
Renal or hepatic dysfunction
Imaging data
Lower EF and left ventricular dilation
Pulmonary hypertension
Right ventricular dysfunction
Mitral regurgitation
Exercise limitation
Six-minute walk distance < 300 m
Peak VO2 < 14 mL/kg/min (not on beta blocker) or
< 12 mL/kg/min (on beta blocker), or < 50% of predicted
on cardiopulmonary exercise testing
Ve/Vco2 slope > 35 on cardiopulmonary exercise testing
CRT = cardiac resynchronization therapy; EF = ejection fraction; ICD = implantable
cardioverter-defibrillator; NYHA = New York Heart Association; Vco2 = production
of carbon dioxide per minute; Ve = ventilatory efficiency (minute ventilation);
VO2 = volume of oxygen consumption; Ve = ventilatory efficiency.

role of heart failure etiology and concomitant

heart disease in decision making in advanced
heart failure
Patients undergoing MCS are typically those with a dilated
left ventricle because cannula positioning is difficult in those
with smaller ventricles. Those with a restrictive or hypertrophic cardiomyopathy pose a technical challenge of placement
of the inflow cannula in the small left ventricular cavity;
however, in those patients in whom implantation of an LVAD
is technically feasible, perioperative and 1-year outcomes do
not seem to differ from those without a restrictive or hypertrophic cardiomyopathy.93 Certain valvular pathologies may
need to be addressed at the time of MCS implantation and
should be fully evaluated prior to surgery. In general, the
aortic valve opens infrequently with continuous-flow left
ventricular support, which may predispose to thrombosis of
the aortic root or of a mechanical aortic prosthesis; therefore,
mechanical aortic prostheses are often replaced with bioprosthetic valves. Aortic regurgitation often worsens following continuous-flow LVAD implantation, which leads to a
continuous circuit of recirculation between the left ventricle
and the LVAD. Therefore, patients with moderate or severe
aortic regurgitation often undergo concurrent oversewing,
closure, or replacement of the aortic valve.94 MR improves in
most patients following LVAD implantation when it is functionally related to left ventricular dilation and does not often
require surgical intervention; in contrast, mitral stenosis
limits LVAD filling and may require replacement with a bioprosthesis.95 Atrial septal defects and patent foramen ovale

cardio
should be closed at the time of LVAD implantation given
the decrease in left atrial pressure following LVAD implantation and the possibility of postoperative right to left shunt,
facilitated by residual right ventricular failure.
Prior to consideration of LVAD implantation, the likelihood of spontaneous recovery should be assessed as patients
who are likely to recover and are able to be stabilized on medical therapy should not have a durable mechanical support
device implanted. Although there is often uncertainty regarding the utility of corrective valvular intervention or coronary
revascularization in patients who have advanced heart failure, those who are likely to benefit with a tolerable level of
surgical risk should have the respective procedures performed to improve ventricular function and possibly obviate
the need for LVAD implantation. In case of clinical decompensation and the need for emergency mechanical support
during or after a proposed revascularization or valvular intervention, it is often prudent to evaluate a patient fully for candidacy of LVAD therapy prior to the proposed procedure.
CRT in inotrope-dependent patients has been associated
with poor outcomes. Implantation of a CRT device in patients
on inotropic therapy may only cause delays in LVAD implantation, risking further end-organ dysfunction or death.96
However, even if some patients were to benefit substantially
from CRT, it makes sense to employ this strategy preemptively as long as the response is assessed early with planned
escalation of therapy if the patient is not responding favorably to CRT.97
right ventricle
Right ventricular failure following LVAD implantation
increases the risk of death and may necessitate the implantation of a right ventricular mechanical support device or
use of prolonged continuous intravenous inotropic therapy.
In addition, ongoing right ventricular dysfunction following
isolated left ventricular mechanical support may pose a persistent limitation to functional capacity and impair end-organ
function. In the current era, right ventricular mechanical
support is available only to those patients who are listed for
cardiac transplantation (as discharge to home is often difficult with biventricular mechanical support), thereby placing
profound importance in identifying patients at risk for postoperative right ventricular failure, especially in those not
eligible for cardiac transplantation. In addition to coexisting
right ventricular dysfunction, patients with a significant
burden of malignant ventricular arrhythmias may also need
to be considered for concomitant right ventricular MCS (as
a bridge to transplantation) as isolated left ventricular
support may be inadequate.
LVAD implantation may not only unmask preexisting
right ventricular dysfunction, but several factors associated
with left ventricular MCS may further impact right ventricular
performance. Ischemic injury associated with cardiopulmonary bypass may at least temporarily worsen right ventricular
function. Increased systemic venous return with left ventricular
mechanical support causes an increase in preload to the
right ventricle, which in concert with a reduction in left ventricular pressure due to direct unloading may shift the interventricular septum toward the left ventricle, causing right
ventricular dilation, worsened tricuspid regurgitation, and
decreased septal contribution to right ventricular output.98

heart failure 17
Assessment of right ventricular function should incorporate a combination of imaging findings (usually with echocardiography), with hemodynamic data (using a pulmonary
artery catheter to assess right atrial pressure and to assess
the ability of the right ventricle to generate pressure and
displace volume, e.g., right ventricular stroke work) and
biochemical data (to assess liver and kidney function, which
may reflect the degree of right ventricular impairment).98 No
single factor has been shown to be adequate in the prediction
of right ventricular failure; therefore, during the evaluation
of a patient referred for left ventricular mechanical support,
imaging, hemodynamic, and biochemical data should all be
comprehensively examined once the patient is medically
optimized.
impact of comorbid conditions
The impact of older age on LVAD outcomes is not entirely
clear. The seventh INTERMACS registry report reflecting
durable MCS implants from 20082014 revealed an increased
perioperative and late mortality in older patients.79 Contrary
to this, a single center reported outcomes of 30 patients over
the age of 70 years with a 97% 30-day and 70% 2-year survival following LVAD implantation, which was no different
from patients at the same institution undergoing LVAD
implantation at an age less than 70 years old.99
Renal and hepatic dysfunction are associated with an
increase in perioperative mortality. Despite this association,
in many patients, renal and hepatic function improve by
6 months following LVAD implantation.100 Patients on hemodialysis have an overall poor prognosis and are likely to
have increased risk of device infection; therefore, many centers consider dialysis a contradication to LVAD implantation.
In patients with reduced renal function, improvement with
a trial of inotropic therapy and lack of significant proteinuria
may suggest reversible azotemia and possibly renal recovery
following LVAD implantation. Chronic elevation in right
atrial pressure resulting in long-standing hepatic congestion
may ultimately lead to hepatic cirrhosis. Patients with cirrhosis are suboptimal candidates for LVAD implantation
given an increase in operative bleeding and perioperative
mortality, especially those who have an elevated Model for
End-Stage Liver Disease (MELD) score or those who are
Child-Pugh class B or C.101 Patients in whom either imaging
or biochemical evidence suggests the possibility of cirrhosis
should undergo liver biopsy.
The presence of peripheral arterial disease at the time of
LVAD implantation may increase the risk of stroke and mesenteric and limb ischemia. This depends largely on the extent
and anatomic location of vascular disease, and in some
cases, this may contraindicate durable LVAD implantation.
Given the hemorrhagic and thrombotic complications that
are common following LVAD implantation, patients with
coagulopathies or hypercoagulable disorders should be considered at increased risk for complications postoperatively.
All patients who undergo LVAD implantation must be able
to tolerate systemic anticoagulation, which at the current
time consists of warfarin with an INR of 2.0 to 3.0 and aspirin
(or an alternate antiplatelet agent); novel oral anticoagulant
agents have not been systematically evaluated.98
Psychosocial barriers, including substance abuse, inadequate social support, and medical noncompliance, should all
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be assessed prior to consideration of LVAD therapy. Another
important consideration is cognitive dysfunction (often
assessed formally with neuropsychological testing); recent
studies have shown that cognitive function, which is often
poor in advanced heart failure, improves significantly after
LVAD implantation. However, advanced cognitive decline
may be a harbinger for poor adherence to the medical regimen
and may complicate LVAD management.102 Poor nutritional
status and frailty increase the risk of death following LVAD
implantation, although no method of improving these parameters to mitigate this risk has been demonstrated.103
outcomes following lvad

Survival
Perioperative (30-day) survival is 95% following LVAD
implantation based on data from the INTERMACS registry.104
Survival following LVAD implantation has improved in
parallel to advances in device technology and in the understanding of appropriate patient selection. One-year survival
following LVAD implantation for transplantation-ineligible
candidates was 53% in the pulsatile LVAD arm of the
REMATCH trial. Most recently, the INTERMACS registry
data from 2008 to 2014 demonstrated a 1-year survival of
80% and median survival of 4 years for patients supported
with a continuous-flow LVAD. The period of time with the
greatest risk of death following LVAD implantation is early
postoperatively and reaches a nadir by 3 months postoperatively. Factors that have the greatest impact on perioperative
mortality include age, female sex, previous stroke, mechanical
ventilation, INTERMACS level 1 or 2, LVAD for destination
therapy, hepatic or renal dysfunction, right ventricular dysfunction or the need for right ventricular mechanical support,
and previous or other concurrent cardiac surgery.76,79

Quality of Life
The impact of LVADs on quality of life and symptoms
related to heart failure has generally been favorable.79 In the
LVAD destination therapy trial, all patients experienced
severe (NYHA III or IV) heart failure symptoms at entry,
and with LVAD support, 80% were rendered asymptomatic
or had only mild symptoms (NYHA class I or II).105 In addition, patients in this trial demonstrated meaningful improvements in heart failurespecific quality of life surveys (Kansas
City Cardiomyopathy questionnaire and the Minnesota
Living with Heart Failure questionnaire) and significant

improvements in 6-minute walk distance by 12 months. This

favorable outlook regarding quality of life should be tempered by the understanding that complications following
LVAD implantation are often unrelated to heart failure;
therefore, heart failurespecific quality of life assessments
may overestimate the benefit of LVAD therapy.

Complications of LVADs
The most common complications in patients supported
with an LVAD are bleeding, LVAD thrombosis, stroke or
systemic thromboembolism, and infection. Following the
30-day perioperative period, bleeding (mostly gastrointestinal)
occurs at a rate of 8 to 23% by 1 year.106 Background antithrombotic therapy with warfarin and an antiplatelet agent
(usually aspirin) in conjunction with an almost universal
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heart failure 18
acquired coagulopathy, related to degradation of large von
Willebrand factor multimers from the shear stress, increases
the overall bleeding risk.107 In addition, similar to Heyde
syndrome (as described in some patients with calcific aortic
stenosis), the effects of low pulsatility of continuous-flow
devices on the microcirculation and an increase in oxidative stress may result in the formation of gastrointestinal
arteriovenous malformations, which provide a nidus for
hemorrhage.
Pump thrombosis occurs with an annual incidence of 6 to
12% and is associated with an increase in neurologic events
and a higher rate of mortality.108110 The subclinical phase of
LVAD thrombosis is characterized by biochemical evidence
of hemolysis caused by turbulent ventricular assist device
flow or elevation in the device power. Later signs include an
inability to unload the left ventricle as determined by noninvasive imaging or invasive hemodynamic evaluation,
decompensated heart failure, and possibly hemodynamic
compromise.111 Lactate dehydrogenase (LDH) is an excellent
(although nonspecific) biomarker of hemolysis and hence
impending or established pump thrombosis. Elevation of
LDH often precedes clinically apparent LVAD pump thrombosis by several weeks and is often monitored as routine
surveillance. Early identification of pump thrombosis in the
subclinical phase usually triggers hospitalization for the intensification of the anticoagulation regimen in the hope of preventing the need for surgical pump exchange, although this
strategy may be fraught with peril.108 Following confirmed
pump thrombosis, there is a twofold increase in 30-day and
6-month mortality.109 Patients who have suspected LVAD
thrombosis and do not undergo LVAD exchange or cardiac
transplantation have a 6-month mortality of 48%, suggesting
that medical therapy for ventricular assist device thrombosis
may be inadequate (or cause harm in the case of thrombolytics). Reoperation (pump exchange) carries a modest 6.5%
perioperative mortality risk and a 65% 2-year survival following exchange.112
Infection is common and occurs in about 20% of patients
following LVAD implantation, which most often involves
the driveline (the main electrical conduit connecting the
internal device to the external controller and batteries).106
Infection associated with LVAD therapy should be treated
aggressively and may require long-term suppressive antibiotics unless the patient undergoes cardiac transplantation or
the device is exchanged. Infection and its inflammatory
sequelae predispose to thrombosis and heighten the risk of
neurologic complications.
Cerebrovascular complications, especially strokes, are
unfortunately common following LVAD implantation, with
an annual incidence exceeding 6%. This complication is
more frequent in those with a previous history of stroke or
atrial fibrillation, in women, and with certain devices. Unless
this complication is reduced with newer devices or enhanced
management strategies, adoption of LVADs to less sick
patients will remain limited.113
In aggregate, by 1 year, 80% of patients undergoing LVAD
implantation will be alive and on average will have an
improved quality of life. Thirty percent will have major
bleeding within the first month and 20% will have major
bleeding over the following 11 months. Ten percent of
patients will have a stroke, 5% will have a device malfunc-

cardio
tion related to thrombosis, 20% will have a serious infection,
and nearly 20% will have ongoing heart failure.106 These
summary statistics are a reasonable way of developing a
well-crafted informed consent process for patients and their
caregivers to improve understanding and expectations postimplantation.
In summary, at the current time, the ideal patients for
durable LVAD implantation either as a bridge to transplantation or as destination (lifetime) therapy are those requiring
continuous inotropic support (INTERMACS 2 or 3) or nearing the need for such therapy (INTERMACS 4). This cohort
of patients should be stable enough to undergo an operation
safely, and there is clear evidence that continued medical
therapy is associated with a very poor prognosis. Patients in
cardiogenic shock who ultimately undergo durable LVAD
implantation have a median survival of 312 years and therefore should not be excluded from consideration of durable
mechanical support (ideally following a period of temporary mechanical support to improve end-organ function and
potentially reduce perioperative risk). LVAD therapy is
evolving and will require a reduction in the rates of complications to apply to less sick heart failure patients. In addition, better understanding of the cost-effectiveness of this
transformative therapy is imperative if this technology is to
be employed more broadly.
palliative options
Patients with stage D heart failure who are not considered
to be candidates for, or do not wish to pursue, cardiac transplantation or LVAD therapy may have options to improve
the overall quality of life.83 For example, continuous inotropic infusion at home via an indwelling central catheter may
be an option. It is important that patients be identified as
having stage D heart failure and a poor prognosis overall
prior to making a commitment to long-term inotropic therapy given the inherent risk of proarrhythmia and possible
increase in mortality.73 Consideration should be given to
deactivation of defibrillator therapy as heart failurerelated
deaths are more common than arrhythmic deaths at the end
stages of heart failure, and the pain and anxiety associated
with defibrillator shocks are not likely to be consistent with
a palliative approach to the end of life.
Financial Disclosures: Sachin P. Shah, MD, and Mandeep R. Mehra, MD, have no
relevant financial relationships to disclose.

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Review Clinical Trial Meta-analysis Guideline
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Acknowledgment
Figure 3 Christine Kenney