Understanding Heart

F a i l u re
Jeremy A. Mazurek, MD, Mariell Jessup, MD*

KEYWORDS
 Heart failure  HFrEF  Ejection fraction  b-Blockers  ACE inhibitors  Neurohormonal blockade
 Treatment

KEY POINTS
 Heart failure (HF) is a progressive, clinical syndrome hallmarked by the inability of the heart to effi-
ciently fill or provide systemic blood flow, resulting in symptoms of fatigue, dyspnea, and ultimately,
significant morbidity and mortality.
 Current guidelines support the use of HF with reduced ejection fraction (HFrEF) and HF with pre-
served ejection fraction to replace systolic HF and diastolic HF, respectively.
 Although neurohormonal and sympathetic inhibition form the foundation of HFrEF medical therapy,
the future role of these and other therapies, such as combined angiotensin-receptor blocker-nepri-
lysin inhibition, implantable cardioverter-defibrillators, and cardiac resynchronization therapy, may
be better optimized with more precise subgroup phenotyping within the HFrEF population.

INTRODUCTION proves to exacerbate fluid overload and cardiac

Heart failure (HF) is a significant public health
concern, affecting nearly 20 million people world-
wide, with a projected 25% increase in prevalence
by 2030.1 Concomitantly, HF-associated health
care expenditures are expected to more than dou-
ble by 2030.1 For example, current US costs for HF
are estimated at $30 billion. More importantly, HF
significantly impacts the lives of those suffering
from this condition, resulting in significant
morbidity and mortality.2
HF is a complex clinical syndrome that can
result from abnormalities in myocardial function
(systolic and diastolic function), valvular or pericar-
dial disease, any of which lead to impaired forward
flow of blood with resultant fluid retention, often
manifesting as pulmonary congestion, peripheral
edema, dyspnea, and fatigue (Box 1).3 This cycle
is fueled by neurohormonal upregulation that
initially serves as a compensatory mechanism to
maintain Frank-Starling mechanics, but ultimately
dysfunction.2,4
The HF guidelines on both sides of the Atlantic
recommend differentiating between HF with
reduced ejection fraction (HFrEF) and HF with pre-
served ejection fraction (HFpEF).2,3 Although HFrEF
and HFpEF each comprise roughly half of the HF
population, they encompass different demo-
graphics and are associated with different propor-
tions of comorbidities and responses to medical
interventions (Table 1).2,58 In fact, although the
exact cutoff for preserved ejection fraction (EF) re-
mains debatable (EF range from >40% to 55%),
the presence of HFrEF suggests a different trajec-
tory in response to current medical HF therapy as
compared with HFpEF, regardless of the exact EF
cut-point for HFpEF used. Moreover, the over-
whelming majority of treatment approaches for HF,
including both medical and device therapy, has tar-
geted or shown benefit specifically in the HFrEF
population as opposed to the HFpEF population.
heartfailure.theclinics.com

This article originally appeared in Cardiac Electrophysiology Clinics, Volume 7, Issue 4, December 2015.
Disclosure Statement: No conflicts of interest.
Cardiovascular Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine,
3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
* Corresponding author. 2 East Perelman Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104.
E-mail addresses: mariell.jessup@uphs.upenn.edu; Jessupm@uphs.upenn.edu

Heart Failure Clin 13 (2017) 119

http://dx.doi.org/10.1016/j.hfc.2016.07.001
1551-7136/17/ 2016 Elsevier Inc. All rights reserved.
2 Mazurek & Jessup
Box 1
Diagnosis of heart failure
The diagnosis of HFrEF requires 3 conditions to
be satisfied:
1. Symptoms typical of HF
2. Signs typical of HF
3. Reduced LVEF
The diagnosis of HFpEF requires 4 conditions to
be satisfied:
1. Symptoms typical of HF
2. Signs typical of HF
3. Normal or only mildly reduced LVEF and LV
not dilated
4. Relevant structural heart disease (LV hyper-
trophy/left atrial enlargement) and/or dia-
stolic dysfunction
Adapted from McMurray JJ, Adamopoulos S, Anker
SD, et al. ESC guidelines for the diagnosis and treat-
ment of acute and chronic heart failure 2012: the
Task Force for the Diagnosis and Treatment of Acute
and Chronic Heart Failure 2012 of the European Soci-
ety of Cardiology. Developed in collaboration with
the Heart Failure Association (HFA) of the ESC. Eur J
Heart Fail 2012;14(8):809; with permission.
This review, in the context of cardiac resynchroniza-
tion therapy (CRT), primarily focuses on patients
with chronic HFrEF.
PATHOPHYSIOLOGY
The syndrome of HF develops from an index event
that results in ventricular dysfunction and ultimately
HF symptoms. The index event, depending on
cause, can be abrupt in onset (ie, myocardial infarc-
tion [MI], viral myocarditis) or may be gradual and
develop over time (ie, left ventricular [LV] hypertro-
phy, genetic).4 This index event results in compen-
satory mechanisms that at first serve to maintain
adequate cardiac output in the face of LV dysfunc-
tion. Over time, however, salt and water retention
become the predominant feature of HF symptoms.
Specifically, the sympathetic nervous system and
neurohormonal cascade (including the renin-
angiotensin-aldosterone system [RAAS], as well
as neprilysin, endothelin, and various inflammatory
cytokines), are upregulated after the index event,
helping to preserve cardiac output by increasing
heart rate and stroke volume.4,9,10 Eventually, this
neurohormonal activation results in deleterious ef-
fects, including LV hypertrophy and remodeling,
pulmonary edema, and excessive vasoconstric-
tion, all of which serve to promote disease progres-
sion.4,9 Levels of endogenous vasodilatory
peptides, including natriuretic peptides, prosta-
glandins, and nitric oxide, are increased in this
setting to counteract the vasoconstrictive effects
of neurohormonal activation, but are often insuffi-
cient (Figs. 1 and 2).4,9 Further perturbations
include abnormalities in cellular signaling, with
increased myocyte apoptosis,11 fibrosis,12 necro-
sis,13 and inflammation,14 which contribute to ven-
tricular remodeling. Ventricular interaction and
valvular function (ie, mitral or tricuspid regurgita-
tion) are compromised, and a predisposition to
the development of supraventricular and ventricu-
lar arrhythmias ensues.9,15
Thus, the HF syndrome is the following:
 The interaction between hemodynamic dysre-
gulation via alterations in myocardial preload,
afterload, and contractility (hemodynamic
model), and
 Neurohormonal disarray (neurohormonal
model) that results in symptom development
and disease progression.4,15
Current treatment approaches, as described
later, target elements within and across these
models to slow disease progression as well as to
improve symptoms and outcomes.
CAUSE OF HEART FAILURE
HF often develops from intrinsic myocardial struc-
tural or functional abnormalities. This dysfunction,
first termed cardiomyopathy in 1957, can result
from a myriad of causes; many remain unknown.16
Clinically, the initial distinction in categorizing a car-
diomyopathy, specifically in the setting of HFrEF, is
to identify whether the myocardial dysfunction is
associated with coronary artery disease (CAD).
CAD can be assessed by either invasive or noninva-
sive means.2,3,17,18 Treatment of ischemic cardio-
myopathy (ICM) with revascularization may
improve or resolve the myocardial dysfunction.
Next, the identification of an underlying systemic
condition or genetic disorder may allow for
disease-specific treatment and may also highlight
other associated sequelae for which the patient
(or relatives) may be at risk. The classification and
subclassification of cardiomyopathies will grow in
importance as therapies may ultimately be cause-
specific, or genetically precise.19,20
Proposed by Maron and colleagues16 and de-
picted in Fig. 3, nonischemic cardiomyopathies
(NICM) are classified into genetic, mixed (in
which some forms may be genetic in origin),
and acquired causes. Within the mixed category,
there is a significant proportion (20%35%) of
those diagnosed with dilated cardiomyopathy
(DCM) who may have familial cardiomyopathy,
 Understanding Heart Failure 3

Table 1
Demographic and clinical characteristics in heart failure with reduced ejection fraction versus heart
failure with preserved ejection fraction

Demographic and Clinical HFrEF HFpEF

Characteristicsa EF <40% (n 5 55,083), 50% EF 50% (n 5 40,354), 36%
Age, y 70 (5880) 78 (6785)
Female 36% 63%
African American race 25% 16%
Medical history
CAD 52% 44%
Pulmonary disease 27% 33%
CKD 48% 52%
Anemia 14% 22%
Diabetes mellitus 22% oral therapy/18% insulin 24% oral therapy/22% insulin
Hypertension 72% 80%
Hyperlipidemia 44% 43%
Atrial fibrillation 28% 34%
CVA/TIA 13% 15%
Obesity (%) 25% 33%
BMI, kg/m2 27 (2332) 29 (2435)
Hemoglobin, g/dL 12.4 (1113.8) 11.5 (10.212.9)
Creatinine, mg/dL 1.3 (11.8) 1.3 (11.9)
Values are displayed as percentages or median (interquartile range) when appropriate.
Abbreviations: BMI, body mass index; CVA/TIA, cerebrovascular accident/transient ischemic attack.
a
Data obtained from the Get with the Guidelines Registry, comprising acute heart failure admissions in 275 hospitals
from 2005 to 2010.
Data from Mentz RJ, Kelly JP, von Lueder TG, et al. Noncardiac comorbidities in heart failure with reduced versus pre-
served ejection fraction. J Am Coll Cardiol 2014;64:2283; and Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in pa-
tients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and
outcomes. Circulation. 2012;126:67.

defined as 2 or more closely related family mem-
bers with DCM.20,21 Currently, 33 genes (31
autosomal and 2 X-linked) are identified in non-
syndromic DCM.20 Pathogenic mutations are
identified in only 30% to 35% of cases of familial
DCM; a negative genetic screen does not rule
out the possibility, especially in the setting of a
highly suggestive family history.20 In addition,
there are a variety of conditions, many of which
that are genetically determined, that can predis-
pose to the development of a secondary NICM,
as enumerated in Box 2.16 This list highlights
the importance of a thorough past medical and
family history to aid in the appropriate classifica-
tion of NICM. More recently, given the ever-
expanding understanding of the genetic basis
for cardiomyopathy, and the varied morphofunc-
tional phenotype a given mutation can display,
the MOGE(S) classification has been pro-
posed.22,23 Two increasingly recognized DCMs
are briefly discussed later, primarily because it
is not clear whether patients with the described
phenotypes respond to CRT.
The incidence of chemotherapy-induced car-
diomyopathy (CHIC) has increased exponentially
over the last decade with the growth in chemother-
apeutic options as well as improved long-term sur-
vival rates of patients treated with cardiotoxic
chemotherapy and radiation.24,25 Beyond the sig-
nificant and numerous cardiovascular (CV) effects
of chemotherapy and radiation exposure,
including premature CAD and peripheral vascular
disease, diabetes and metabolic syndrome, hy-
pertension, valvular disease, conduction disease,
pericardial disease, and restrictive cardiomyopa-
thy, several chemotherapeutic agents have been
implicated in the development of CHIC.24 As noted
in Table 1, CHIC is a form of secondary DCM,
which occurs in a dose-dependent manner after
exposure to chemotherapies, including the
following:
 Anthracyclines,
 Cyclophosmamide,
 Monoclonal antibodies, including trastuzu-
mab (monoclonal antibody targeting human
4 Mazurek & Jessup

Fig. 1. Pathophysiology of HF. After an initial event resulting in myocardial injury, there are alterations that occur
at the myocardial, vascular, and neurohormonal level. These changes initially serve in a compensatory fashion,
but over time result in further dysfunction and disease progression. ANP, atrial natriuretic peptide; BNP, B-type
natriuretic peptide; CHF, congestive heart failure; NOS, nitric oxide synthase; RAS, renin-angiotensin system;
ROS, reactive oxygen species; SNS, sympathetic nervous system. (From Kaye DM, Krum H. Drug discovery for heart
failure: a new era or the end of the pipeline? Nat Rev Drug Discov 2007;6(2):128; with permission.)

epidermal growth factor receptor 2 [HER2] in therapy.2,2426 Although a proportion of pa-

HER21 breast cancer), and tients can develop HFrEF acutely with initia-
 Proteasome inhibitors, of which the latter 2 tion of therapy, all those exposed to these
are often reversible with discontinuation of agents are at risk for HF for years after

Fig. 2. An updated schema showing the production and biological effect of several angiotensin peptides. AT-R,
angiotensin type receptor; mas-R, mas oncogene G protein-couples receptor; NEP, neprilysin. (From Ferrario CM,
Strawn WB. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular
disease. Am J Cardiol 2006;98(1):122; with permission.)
 Understanding Heart Failure 5

Fig. 3. Proposed classification of primary cardiomyopathies by cause. *May be genetic or nongenetic; familial dis-
ease with a genetic origin has been increasingly reported. ARVC/D, arrhythmogenic right ventricular cardiomyopa-
thy/dysplasia; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LVNC, left ventricular noncompaction;
PRKAG2, g-2-regulatory subunit of the AMP-activated protein kinase; SQTS, short QT syndrome; SUNDS, sudden un-
explained nocturnal death syndrome. (Reprinted with permission from Maron BJ, Towbin JA, Thiene G, et al.
Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific
Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care
and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups;
and Council on Epidemiology and Prevention. Circulation 2006;113:1810. 2006, American Heart Association, Inc.)

chemotherapy. The onset and risk of symp-
tomatic HF are w1% to 2% at 10 years and
increase to 10% to 15% at 25 years or more.24
Similarly, the exponential increase in the inci-
dence of metabolic syndrome, specifically the
obesity and diabetes mellitus (DM) epidemics,
has impacted and shaped the trajectory of HF
development and progression over the last 2 de-
cades.2 Both obesity and DM are independent
risk factors for the future development of HF,27,28
with the latter conferring a worse outcome in those
with established HF.29 Several mechanisms
describing obesitys role in HF development have
been proposed, including the effects of increased
circulating blood volume,30 myocardial lipotoxicity,
and myocardial lipid-deposition resulting in
myocardial dysfunction.31,32 Diabetic cardiomyop-
athy develops via several mechanisms, including
increased oxidative stress,33 endothelial dysfunc-
tion,34 accelerated atherosclerosis,35 advanced
glycation end-products resulting in increased
myocardial stiffness and cellular dysfunction,36,37
and alterations in myocardial metabolism and inef-
ficient glucose utilization in the setting of insulin
resistance.35,38
CURRENT APPROACH TO HEART FAILURE
STAGING
First described in 1928, the New York Heart Associ-
ation (NYHA) functional classification remains a
commonly used system to describe functional ca-
pacity in HF.2,39 As described in Table 2, this system
subjectively assesses disease-related symptoms
and exercise capacity and stratifies patients into 4
categories ranging from lack of symptoms with ordi-
nary activity (class I) to the inability to perform any
physical activity without symptoms and with symp-
toms at rest (class IV).2 Although this system is an
effective way of communicating symptom severity,
it does not identify those who are at risk for the devel-
opment of HF. In addition, the NYHA classification
may downgrade those who are asymptomatic
6 Mazurek & Jessup

Box 2 Rheumatoid arthritis

Secondary cardiomyopathies Scleroderma
Infiltrativea Polyarteritis nodosa
Amyloidosis (primary, familial autosomal Electrolyte imbalance
dominant,b senile, secondary forms) Consequence of cancer therapy
Gaucher diseaseb
Anthracyclines: doxorubicin (adriamycin),
Hurler diseaseb daunorubicin
Hunter diseaseb Cyclophosphamide
c Trastuzumab and other monoclonal antibody-
Storage
based tyrosine kinase inhibitors
Hemochromatosis
Radiation
Fabry diseaseb
a
Glycogn storage diseaseb (type II, Pompe) Accumulation of abnormal substances between
myocytes (ie, extracellular).
b
Niemann-Pick disease b
Genetic (familial) origin.
c
Accumulation of abnormal substances within myo-
Toxicity cytes (ie, intracellular).
Drugs, heavy metals, chemical agents Reprinted with permission from Maron BJ, Towbin JA,
Thiene G, et al. Contemporary definitions and classifica-
Endomyocardial tion of the cardiomyopathies: An American Heart Asso-
ciation Scientific Statement from the Council on Clinical
Endomyocardial fibrosis Cardiology, Heart Failure and Transplantation Commit-
Hypereosinophilic syndrome (Loeffler tee; Quality of Care and Outcomes Research and
endocarditis) Functional Genomics and Translational Biology Interdis-
ciplinary Working Groups; and Council on Epidemiology
Inflammatory (granulomatous) and Prevention. Circulation 2006;113:1814. 2006,
American Heart Association, Inc.
Sarcoidosis
Endocrine
Diabetes mellitusb despite significant underlying disease. An alterna-
tive was proposed in 2001 by the American College
Hyperthyroidism
of Cardiology Foundation (ACCF) and American
Hypothyroidism Heart Association (AHA): a staging system to serve
Hyperparathyroidism in a complementary fashion to the NYHA functional
Pheochromocytoma classification.40 As listed in Table 2 and depicted
in Fig. 4, the ACCF/AHA HF staging system ranges
Acromegaly from those at risk of HF to those patients with severe
Cardiofacial HF. This staging system allows for preventative and
Noonan syndromeb treatment recommendations that are stage-specific
(Figs. 4 and 5).
Lentiginosisb
Neuromuscular/neurologic CURRENT APPROACH TO HEART FAILURE
Friedreichs ataxia b TREATMENT
Duchenne-Becker muscular dystrophyb Beyond those with stage A HF, in which the current
Emery-Dreifuss muscular dystrophy b approach is largely control of modifiable risk fac-
tors (for CAD, diabetes, hypertension, and other
Myotonic dystrophyb
risk factors), a remarkable evidence base has
Neurofibromatosisb amassed over the last 3 decades informing the
Tuberous sclerosisb approach to the treatment of stage B HF and
beyond (Figs. 46, Table 3). As evident from
Nutritional deficiencies
Figs. 46, treatment recommendations for chronic
Beriberi (thiamine), pellagra, scurvy, sele- HFrEF are largely uniform across the American and
nium, carnitine, kwashiorkor European guidelines, although differences exist,
Autoimmune/collagen including the use of the ACCF/AHA HF staging sys-
tem, and with regard to the role of second-line
Systemic lupus erythematosis
agents (ie, ivabradine, hydralazine-isosorbide dini-
Dermatomyositis trate) in the treatment of HFrEF.2,3

Table 2
Summary and comparison of the American College of Cardiology Foundation and American Heart
Association stages of heart failure and New York Heart Association functional classifications
ACCF/AHA Stages of HF
A At high risk for HF but without structural
heart disease or symptoms of HF
B Structural heart disease but without signs
or symptoms of HF
C Structural heart disease with prior or
current symptoms of HF
D Refractory HF requiring specialized
interventions
Adapted from Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a
report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
J Am Coll Cardiol 2013;62(16):e155; with permission.
PHARMACOLOGIC THERAPY
Angiotensin-Converting Enzyme Inhibitors
and Angiotensin II Receptor Blockers
Beginning in the 1980s, and continuing for the bet-
ter part of a decade, several clinical trials emerged
solidifying the beneficial effects of angiotensin-
converting enzyme inhibitors (ACEI) in the
improvement of mortality as well as symptoms,
hemodynamics, and ventricular dysfunction seen
in HFrEF (see Table 3).4144 The aggregate of
these trials reveal an w25% reduction in mortality
in those treated with ACEI as compared with con-
trols.45 Furthermore, ACEI therapy has been
shown to be beneficial in those with asymptomatic
LV dysfunction (stage B), in both the setting of
NICM and after MI.43,44 Angiotensin-receptor
blocker (ARBs), although less extensively and indi-
vidually studied in large HF trials, seem to display
similar favorable effects in HFrEF and are often
used if ACEI are not well-tolerated.2,46,47 In addi-
tion, ARBs added to a background of ACEI (espe-
cially in the context of aldosterone antagonists) do
not confer a mortality benefit in HF and increase
the risk of adverse events.2,3,4749
Aldosterone Antagonists
Elevations in aldosterone levels produce nega-
tive effects on myocardial and vascular structure
Understanding Heart Failure 7
NYHA Functional Classification
None
I No limitation of physical activity. Ordinary
physical activity does not cause symptoms
of HF.
I No limitation of physical activity. Ordinary
physical activity does not cause symptoms
of HF.
II Slight limitation of physical activity.
Comfortable at rest, but ordinary physical
activity results in symptoms of HF.
III Marked limitation of physical activity.
Comfortable at rest, but less than ordinary
activity causes symptoms of HF.
IV Unable to carry on any physical activity
without symptoms of HF, or symptoms of HF
at rest.
IV Unable to carry on any physical activity
without symptoms of HF, or symptoms of HF
at rest.
and function independent of those induced by
angiotensin II.50 In addition, although initial treat-
ment with ACEI or ARBs reduces aldosterone
levels, over time the phenomenon of aldoste-
rone escape occurs, resulting in renewed eleva-
tions of aldosterone levels.51 This background
led to several studies evaluating the role of aldo-
sterone blockade in HFrEF in those already on
standard HF therapy including ACEI/ARB and
b-blockers (see Table 3). The result was a signif-
icant, 30% decrease in the risk of death in pa-
tients with a spectrum of symptoms.50,52,53
Current guidelines recommend consideration of
aldosterone antagonists in patients with a serum
creatinine less than 2.5 mg/dL (or an estimated
glomerular filtration rate >30 mL/min/1.73 m2),
without recent worsening and serum potassium
less than 5.0 mEq/L without a history of severe
hyperkalemia.2
b-Blockers
The sympathetic nervous system activation in HF
has many deleterious effects, including the
following:
 Increased vasoconstriction and LV afterload,
 Adverse cardiac remodeling and fibrosis,
 Pro-arrhythmic effects,
 Potentiation of the RAAS.
8 Mazurek & Jessup

Fig. 4. ACCF/AHA heart failure stages with recommended therapy by stage. AF, atrial fibrillation; GDMT,
guideline-directed medical therapy; HRQOL, health-related quality of life; HTN, hypertension; ICD, implantable
cardioverter-defibrillator; LVH, left ventricular hypertrophy. (Adapted from Yancy CW, Jessup M, Bozkurt B,
et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Car-
diology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol
2013;62(16):e193; with permission.)

When added to established background HF
therapy including ACEI and diuretics, b-blockers
result in an w30% risk reduction in mortality along
with an improvement in HF symptoms, reduced
HF hospitalizations, and improvement in clinical
status (see Table 3).5458 These benefits do not
seem to be a class effect; studies evaluating bu-
cindolol (vs placebo) and metoprolol tartrate (as
compared with carvedilol) did not result in similar
improvements.58,59
Nearly 90% of patients studied were on back-
ground b-blocker therapy, with the effect of ivab-
radine maintained regardless of b-blocker
dose.61 Although already approved and in use in
Europe,3 ivabradine only recently obtained Food
and Drug Administration (FDA) approval in the
United States for use in HFrEF to reduce HF hos-
pitalization in patients with resting heart rate of
70 beats per minute or more and on maximally
tolerated b-blocker therapy.62

Ivabradine Hydralazine and Isosorbide Dinitrate

Ivabradine is a novel If current inhibitor in the
sinoatrial node. This current, a mixed sodium-
potassium inward current, is activated by the sym-
pathetic nervous system, resulting in enhanced
pacemaker activity and increased heart rate. Inhi-
bition with ivabradine results in reduction in heart
rate and myocardial oxygen demand. Ivabradine
was studied in HFrEF in the SHIFT trial, which
demonstrated an 18% reduction in the composite
of CV death or HF hospitalization (see Table 3).60
Initially studied in the V-HeFT I trial (in comparison
to prazosin and placebo), combination hydralazine
and isosorbide dinitrate (HISDN) therapy resulted
in an improvement in left ventricular ejection
fraction (LVEF) and exercise capacity, with a mor-
tality reduction that was intermediately signifi-
cant.63 Based on subsequent data,6466 the
A-HeFT trial studied the role of HISDN therapy in
African American patients with HFrEF (already on
background ACEI/ARBs and b-blockers) and
 Understanding Heart Failure 9

Fig. 5. Guideline-directed medical therapy for stage C HFrEF. Hydral-Nitrates, hydralazine and isosorbide dini-
trate; LOE, level of evidence. (Adapted from Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline
for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines. J Am Coll Cardiol 2013;62(16):e173; with permission.)

found that compared with placebo, HISDN re- DEVICE THERAPY

sulted in significant improvements in survival and
HF hospitalization among other endpoints (see Ta-
ble 3).67 This trial underscores the potential for
more precise HF therapy in the future.
Digoxin
Digoxin is a cardiac glycoside that inhibits the
sodium-potassium ATPase resulting in increased
sodium concentrations, increasing intracellular
calcium via the sodium-calcium exchanger.
Although digoxin has been used for the treatment
of HF for centuries, the DIG trial is the only ran-
domized, placebo-controlled trial powered to
assess the effect of digoxin on morbidity and
mortality in HF. Overall, digoxin did not reduce
mortality, although it led to a reduction in all-
cause and HF hospitalization (see Table 3).68
Subanalysis of this trial has revealed increased
morbidity and mortality with digoxin levels greater
than 0.8 ng/mL,69,70 as well as in women, the
elderly, and those with compromised renal
function.69,71
Implantable Cardioverter-Defibrillators
Patients with HFrEF are at increased risk for ven-
tricular arrhythmias and sudden cardiac death
(SCD). For this reason, over the last 20 years,
ICDs have been studied for both primary and sec-
ondary prevention in the setting of ICM and NICM
across several clinical trials and have emerged as
extremely effective in reducing SCD in these
populations.2,7276
The Multicenter Automatic Defibrillator Implanta-
tion Trial (MADIT) was the first to show a mortality
benefit of ICD therapy as compared with medical
therapy. This study included patients with ICM and
LVEF less than or equal to 35% and asymptomatic
nonsustained ventricular tachycardia (VT). ICD im-
plantation resulted in a 54% relative risk reduction
for mortality over 5 years.72 The MADIT-II trial evalu-
ated a similar population (LVEF <30%) on more con-
ventional HF therapy, at least 1 month after MI or
3 months after revascularization, but did not require
electrophysiology study for study entry. MADIT-II re-
vealed a 31% relative risk reduction in death over
20 months of therapy.73 The Sudden Cardiac Death
10 Mazurek & Jessup
 Understanding Heart Failure 11

in Heart Failure Trial (SCD-HeFT) randomized pa-
tients with ICM or NICM (LVEF 35%) to ICD, amio-
darone, or placebo in addition to conventional HF
therapy. This trial found a significant, 23% relative
risk reduction in death for the ICD arm compared
with placebo, with no benefit in the amiodarone
arm compared with placebo (see Table 3).74 Data
from subanalyses of these77,78 and other trials,79,80
as well as from real world registries, highlight the
lack of benefit, and even increased risks associated
with inappropriate ICD implantation.81 Furthermore,
several patient populations were not included or
were underrepresented in these seminal trials,
including those with significant chronic kidney
disease/end-stage renal disease (CKD/ESRD),82
as well the elderly83,84 and those with a host of other
life-limiting medical comorbidities.82,85
Cardiac Resynchronization Therapy
Fifty percent of patients with HFrEF develop con-
duction disease from a variety of mechanisms,
which can result in electrical dyssynchrony and
further compromise ventricular efficiency.8688 As
highlighted by the contents of this dedicated vol-
ume on CRT, restoration of electrical and mechan-
ical coordination with CRT have led to significant
improvements in LV structure and function, exer-
cise capacity, and quality of life, with reductions
in HF hospitalization and mortality.8997 These
changes are reflected in improvements in myocyte
function as well, with enhanced calcium handling,
normalization of the action potential duration, in
addition to improved mitochondrial energetics,
among others.98,99
Although the initial studies evaluated those with
more severe and symptomatic HF (NYHA class
IIIIV),8992 more recent studies have further
clarified the populations who stand to benefit
from CRT, including those with milder HF symp-
toms.9395 Subgroups more likely to improve with
CRT include women, those with a left bundle
branch block, and those with a QRS duration of
150 ms or more.76,100103 More recently, given the
increase in recognition of CHIC, the MADIT-CHIC
trial is underway to assess the benefit of CRT in
this population.104 Several important CRT trials
and their key findings are listed in Table 3.
ADVANCED THERAPIES
It is estimated that 5% of patients with HF have
end-stage, or stage D disease, carrying 1- and
5-year mortality rates of 28% and 80%, respec-
tively.105 These patients are characterized by fea-
tures of worsening symptoms, objective evidence
of reduced exercise capacity, fluid retention,
recent HF admissions, biomarker and echocardio-
graphic evidence of severe cardiac dysfunction,
as well as inability to tolerate standard HF ther-
apy.106,107 These signs and symptoms should
prompt the clinician to consider referral for more
advanced HF therapies (Box 3).107 Stage D pa-
tients may consider options including mechanical
circulatory support (MCS; as destination ther-
apy108,109 or bridge to transplant),110,111 cardiac
transplantation, or palliative/hospice care. Joint
decision-making between the patient, their family,
and the care team is necessary in this setting.
Given the scarcity of available hearts suitable for
donation, MCS has grown over the last 2 decades,
offering the potential for increased quantity and
quality of life for patients with end-stage HF.
Although left ventricular assist devices are the
most common form of MCS, other devices,
including the total artificial heart, represent a

=
Fig. 6. European Society of Cardiology 2012 Guidelines: treatment options for patients with chronic symptomatic
HFrEF. CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker;
H-ISDN, hydralazine and isosorbide dinitrate; HR, heart rate; ICD, implantable cardioverter-defibrillator; LVAD, left
ventricular assist device; MR antagonist, mineralocorticoid receptor antagonist. aDiuretics may be used as needed to
relieve the signs and symptoms of congestion but they have not been shown to reduce hospitalization or death.
b
Should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose. cAsympto-
matic patients with an LVEF less than or equal to 35% and a history of MI should be considered for an ICD. dIf miner-
alocorticoid receptor antagonist is not tolerated, an ARB may be added to an ACE inhibitor as an alternative.
e
European Medicines Agency has approved ivabradine for use in patients with a heart rate greater than or equal
to 75 bpm. May also be considered in patients with a contraindication to a b-blocker or b-blocker intolerance.
f
See Section 9.2 of the ESC guidelines for detailsindication differs according to heart rhythm, NYHA class, QRS
duration, QRS morphology, and LVEF. gNot indicated in NYHA class IV. hDigoxin may be used earlier to control
the ventricular rate in patients with atrial fibrillationusually in conjunction with a b-blocker. iThe combination
of hydralazine and isosorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor
or an ARB. (Adapted from McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treat-
ment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic
Heart Failure 2012 of the European Society of Cardiology. developed in collaboration with the Heart Failure Asso-
ciation (HFA) of the ESC. Eur J Heart Fail 2012;14(8):821; with permission.)
 12
Mazurek & Jessup
Table 3
Summary of selected landmark trials in heart failure therapy

Year Study Title Study Drug Key Findings

41
ACEI 1987 CONSENSUS Enalapril vs placebo 27% overall RRR death
1991 SOLVD Treatment42 Enalapril vs placebo 16% RRR death
1992 SOLVD Prevention43 Enalapril vs placebo Asymptomatic HFrEF patients; 29% RRR death or
development of HF
1992 SAVE44 Captopril vs placebo Post-MI, HFrEF; 19% RRR death
ARB 2001 Val-HeFT48 Valsartan vs placebo No mortality benefit but improved CV morbidity, QOL
2003 VALIANT47 Valsartan vs valsartan 1 captopril HFrEF post-MI; valsartan noninferior to captopril, increased
vs captopril adverse events with valsartan 1 captopril
2003 CHARM-Alternative46 Candesartan vs placebo Patients intolerant to ACEI; 23% RRR in CV death or HF
hospitalization
2003 CHARM-Added49 Candesartan vs placebo ARB added to open-label ACEI; 15% RRR CV death and
unplanned HF admission
Aldosterone 1999 RALES50 Spironolactone vs placebo Severe HFrEF (11% on background b-blocker); 30% RRR death
antagonists 2003 EPHESUS52 Eplerenone vs placebo HFrEF post-MI (75% on b-blocker); 15% RRR death
2010 EMPHASIS-HF53 Eplerenone vs placebo Mild HFrEF (87% on b-blocker); 34% RRR death
b-Blockers 1996 US Carvedilol Study54 Carvedilol vs placebo 65% RRR death
1999 CIBIS-II55 Bisoprolol vs placebo 32% RRR death
1999 MERIT-HF56 Metoprolol succinate vs placebo 34% RRR death
2001 COPERNICUS57 Carvedilol vs placebo 35% RRR death
2003 COMET58 Carvedilol vs metoprolol tartrate 17% RRR death
If current 2010 SHIFT60 Ivabradine vs placebo 18% RRR CV death and HF hospitalization
inhibitor
HISDN 1986 V-HeFT I63 HISDN vs prazosin vs placebo NS RRR death. Improvements in EF and exercise capacity with
HISDN
1991 V-HeFT II64 Enalapril vs HISDN NS RRR death. Improvements in EF and exercise capacity with
HISDN
2004 A-HeFT67 HISDN vs placebo African Americans with HFrEF; 40% and 33% RRR death and
first HF admission, respectively
 Angiotensin-neprilysin 2014 PARADIGM-HF117 LCZ696 (valsartan 1 sacubitril) 18% RRR CV death or first HF hospitalization
inhibitor vs enalapril
ICDs 1996 MADIT72 ICD vs OMT ICM (EF 35%), asymptomatic NSVT, inducible VT/VF on EPS.
54% RRR death
2002 MADIT-II73 ICD vs OMT ICM (EF 30%), no need for VT/VF on EPS, 31% RRR death
2005 SCD-HeFT74 ICD vs amiodarone vs placebo NICM or ICM (EF <35%), 23% RRR death in ICD vs placebo
CRT 2001 MUSTIC89 CRT vs control Small trial (n 5 67), NYHA class III, EF <35%, QRS >150 ms,
crossover design, improvements in 6MWD, QOL, peak VO2
2002 MIRACLE90 CRT vs control NYHA class III-IV, EF 35%, QRS >130 ms; significant
improvement in functional capacity, QOL, echo parameters
and death/worsening HF with CRT
2004 COMPANION91 CRT vs CRT-D vs control ICM or NICM, NYHA III-IV, EF 35%, QRS 120 ms, 20% RRR
combined mortality and hospitalization in CRT or CRT-D vs
control; mortality significant in CRT-D vs control only
2005 CARE-HF92 CRT vs control 36% RRR death; improvements in LV size/function, MR, NYHA
class, QOL
2008 REVERSE93 CRT (CRT-D or CRT-P) vs ICD NYHA class III, EF 40%, QRS  120 ms
Overall, NS 1o end-point (worsened HF), but significant
reduction in time-to-first HF hospitalization (hazard ratio:
0.47, P 5 .03) at 12 mo
At 24 mo, 44% RRR worsening HF and significant reduction
In time-to-first HF hospitalization or death (hazard ratio:
0.38; P 5 .003)
2009 MADIT-CRT94 CRT-D vs ICD NYHA I-II, EF 30%, QRS 130 ms, 34% RRR combined death
and worsening HF
2010 RAFT95 CRT-D vs ICD NYHA IIIII, EF 30%, QRS 120 ms, 25% RRR combined
death and HF hospitalization and death alone

Understanding Heart Failure

Abbreviations: 6MWD, 6-min walk distance; CRT-D, cardiac resynchronization therapy-defibrillator; CRT-P, cardiac resynchronization therapy-pacing; EPS, electrophysiology study;
ICD, implantable cardioverter-defibrillator; MR, mitral regurgitation; NS, not significant; NSVT, nonsustained ventricular tachycardia; OMT, optimal medical therapy, QOL, quality
of life; RRR, relative risk reduction; VO2, oxygen consumption.

13
14 Mazurek & Jessup
biventricular MCS option, although they currently
comprise less than 5% of all MCS implants.107
MCS devices, however, are not free of complica-
tions, including device malfunction, infection,
stroke, bleeding, thrombosis, and death.112,113
BIOMARKER ASSESSMENT IN HEART FAILURE
There has been significant growth in the identifica-
tion and understanding of biomarkers and their
role in the diagnosis, management, and prognosti-
cation of HF.114116 Such molecules, most notably
B-type natriuretic peptide (BNP) or NT-proBNP,
have been shown to be prognostically powerful,
although their role in optimizing HF management
and improving survival and readmission rates has
been less clear.
THE FUTURE
The publication of the Angiotensin-Neprilysin Inhi-
bition versus Enalapril in HF (PARADIGM-HF) trial,
evaluating combined ARB/Neprilysin-inhibition
(LCZ696) as compared with enalapril alone in HFrEF
Box 3
Triggers for referral for ventricular assist device
evaluation
Inability to wean inotropes or frequent ino-
trope use
1 1
Peak VO2 <14 to 16 mL kg min or less than
50% predicted
Two or more HF admissions in 12 mo
Worsening right HF and secondary pulmonary
hypertension
Diuretic refractoriness associated with wors-
ening renal function
Circulatory-renal limitation to ACE inhibition
Hypotension limiting b-blocker therapy
NYHA class IV symptoms at rest on most days
Seattle HF model score with anticipated mortal-
ity greater than 15% at 1 y
Six-minute walk distance less than 300 m
Persistent hyponatremia (serum sodium <134
mEq/L)
Recurrent, refractory ventricular
tachyarrhythmias
Cardiac cachexia
Abbreviation: VO2, oxygen consumption.
Adapted from Stewart GC, Givertz MM. Mechanical
circulatory support for advanced heart failure: pa-
tients and technology in evolution. Circulation
2012;125:1311; with permission.
patients may be seen as representative of a new era
of HF therapeutic discovery.117 The new drug re-
sulted in an additional 18% relative risk reduction
in the combined primary endpoint (CV death or first
HF hospitalization) over those treated with ACEI,
with similar significant reductions in the individual
components of the primary endpoint (see Table 3).
Several other promising drugs are in clinical trials as
well, including serelaxin,118 omecamtiv mecar-
bil,119,120 and LCZ596 in HFpEF.121
Other areas of continued research include the
following:
 The role of implantable hemodynamic and
biomarker-guided monitoring in HFrEF122124
 Honing the ability to maximize response to
both pharmacotherapy125,126 and device ther-
apy,98,127 specifically assessing the role/
benefit of these therapies in patients with sig-
nificant comorbidities, (ie, CKD/ESRD)128
 Clarifying the role of stem cell therapy in
HFrEF129
 Expanding the understanding of the genetic
and epigenetic factors as well as the identifi-
cation of potential novel screening, classifica-
tion, and treatment targets in HFrEF19,23
 Assessing the role and methods of rhythm
control in patients with HFrEF and atrial fibril-
lation,130 given the coexistence of these con-
ditions and their association with worse
outcomes131
Last, while beyond the scope of this review,
there has been increased interest in optimizing
the authors approach and identifying novel treat-
ment targets in acute decompensated HF118,120
as well as improving MCS decision-making and
heart transplant donor allocation in those with
advanced disease.107,132
SUMMARY
Despite significant advances in the understanding
of the pathophysiology and treatment of HF over
the last 3 decades, HF is a progressive condition
with a rising prevalence, and the primary cause
for hospitalization among the elderly. In addition
to the current evidence-based treatment ap-
proaches, further study is required to improve
the ability to identify, treat, and ultimately prevent
this condition.
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