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5
Heart Failure and Cardiomyopathy
Daniel J. Levine, Hyeon-Ju Ryoo Ali, Rayan Yousefzai
DEFINITION AND CLASSIFICATION
Heart failure (HF) is a clinical syndrome defined by inability of the
heart to maintain output under normal filling pressures and/or impairment in relaxation of ventricles causing an increase in filling pressures.
Patients experience fatigue and exercise intolerance if cardiac output is
low and dyspnea and peripheral edema if the ventricular filling pressure is elevated. There are numerous ways to classify HF—by the type
of cardiac impairment, causes of cardiomyopathy, patient’s symptoms,
or hemodynamic profiles.
Ejection Fraction
Most patients with HF have disorders in both systolic and diastolic
function. However, ejection fraction (EF) is an important distinguishing characteristic in most clinical trials and, therefore, in guidelines for
therapy. By imaging, cardiac function can be categorized as reduced
EF (<40%) or preserved EF (≥50%). Patients with midrange EF (40%
to 50%) are treated similarly to patients with reduced EF. HF with
reduced EF (HFrEF) is associated with significant morbidity and mortality, especially in the elderly and those with severely low EF (<30%).
HF with preserved EF (HFpEF) is less well studied with fewer effective
targeted therapies. Increasing awareness of HFpEF has led to recognition of its prevalence with associated morbidity and mortality and the
need for more research into optimal management.
Causes
Table 5.1 lists the common causes of cardiomyopathy leading to HF.
Ischemic cardiomyopathy is the most common cause of HF and is estimated to account for about 60% of all HF admissions in the United
States. This serves as a basis for clinical practice. Patients who present with new cardiomyopathy may undergo cardiac catheterization to
exclude underlying coronary artery disease (CAD). Common causes
of nonischemic cardiomyopathy include hypertension, chemotherapy,
substance use, familial cardiomyopathy, and systemic disorders affecting the heart, such as amyloidosis and hemochromatosis. Worldwide,
infections are a common cause of nonischemic cardiomyopathy including Chagas disease (endemic in South America), tuberculosis, and HIV.
Additional nonmyocardial processes that lead to HF include primary pericardial disorders. Pericardial tamponade limits the compliance of the heart, resulting in elevated filling pressures. Other
causes include radiation-induced pericarditis, viral pericarditis,
postsurgical pericardial thickening, and idiopathic fibrosis of the
pericardium.
Valvular pathology including regurgitant and stenotic lesions can
also lead to signs and symptoms of HF. Undetected, they can lead to
morphologic changes in ventricular size and function. Most studies of
HF exclude patients with uncorrected valvular diseases. Diagnosis and
treatment of valvular heart disease is reviewed separately (see Chapter
7, “Valvular Heart Disease”).
Types of Cardiomyopathy
Historically, cardiomyopathy has been classified morphologically as
“dilated,” “hypertrophic,” and “restrictive.” Dilated cardiomyopathy commonly leads to impairment in systolic function, or HFrEF.
Common causes of dilated cardiomyopathy include myocardial infarction or infectious myocarditis.
Ventricular hypertrophy causes impairment in relaxation of ventricles, elevated filling pressures, and HFpEF. The most common cause of
hypertrophy of ventricles is long-standing hypertension. Older women
are at higher risk, as well as patients with diabetes, atrial fibrillation,
obesity, hyperlipidemia, and CAD. Hypertrophic cardiomyopathy
(HCM) is a genetic disorder in which a mutation in the sarcomeric
proteins leads to thickening of ventricles and impaired filling. Patients
with known family history of HCM should be tested by genetic analysis; current tests achieve a diagnostic yield of 30% to 60%. More than
130 genes associated with cardiomyopathy and arrhythmias have been
identified. Genetic testing should be performed in centers with experienced geneticists and genetic counselors.
Restrictive cardiomyopathy also impairs ventricular relaxation and
leads to HFpEF. This type of cardiomyopathy can be due to fibrosis
as in radiation heart disease, or deposition of insoluble proteins as in
amyloidosis. Restrictive cardiomyopathy is much less common than
the other two types.
High-output HF is an under-recognized entity. It is characterized
by an increased cardiac output that still fails to meet the metabolic and
perfusion demands. Possible causes include obesity, anemia, hyperthyroidism, vitamin B1 deficiency, arteriovenous shunts and liver disease.
Functional Impairment
HF is a clinical syndrome with management strategies targeted to
patients’ symptoms and function status. Thus, it is paramount to have
a unified language to stratify patients’ degree of symptoms. Table 5.2
displays two classification methods: the “stages” as defined by the
American College of Cardiology Foundation and the American Heart
Association (ACCF/AHA) and the “classes” as defined by the New
York Heart Association (NYHA).
ACCF/AHA Stages of HF
Patients in ACCF/AHA stage A have risk factors—such as hypertension, diabetes, metabolic syndrome, history of cardiac toxins, and
family history of cardiomyopathy—without the diagnosis of CAD or
cardiac remodeling. In stage B, patients may have prior history of MI
or evidence of cardiomyopathy, but do not have symptoms. Stage C
43
44 SECTION II Cardiovascular Disease
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TABLE 5.1 Causes of Cardiomyopathy
Myocardial infarction
Infection
HIV
Lyme
Chagas
Viral myocarditis
Tuberculosis
Iatrogenic
Chemotherapy: bleomycin, doxorubicin (Adriamycin)
Antiretroviral medications
Radiation
Phenothiazines
Chloroquine
Clozapine
Toxins
Alcohol
Cocaine
Methamphetamines
Cobalt, lead, lithium, mercury, carbon monoxide, beryllium
Endocrine and metabolic
Thyroid dysfunction
Thiamine deficiency
Pellagra
Hypophosphatemia, hypocalcemia, uremia
Inflammatory
Systemic lupus erythematosus
Scleroderma
Rheumatoid arthritis
Giant cell arteritis
Kawasaki disease
Infiltrative cardiomyopathy
Amyloidosis
Sarcoidosis
Hemochromatosis
Other structural
Valvular disease: progressive stenosis or regurgitation, acute chordae
tendineae rupture, thrombosis of replaced valve
Infective endocarditis
Takotsubo cardiomyopathy
Idiopathic dilated cardiomyopathy
Idiopathic restrictive cardiomyopathy
Peripartum cardiomyopathy
Arrhythmogenic right ventricular dysplasia
Congenital heart disease
Fabry disease
Danon disease
Friedreich’s ataxia
Myotonic dystrophy
Duchenne-Becker muscular dystrophy
Rhythm
Tachy-mediated cardiomyopathy
Pacing-mediated cardiomyopathy
constitutes clinical signs and symptoms of HF, while stage D encompasses patients whose HF is refractory to appropriate therapy.
NYHA Functional Classification of HF
The NYHA classification characterizes functional impairment of patients
in symptomatic HF (ACCF/AHA stages C and D). Class I patients are
asymptomatic with ordinary activity and may also fall under stage B.
Patients in class II have some limitation at moderate levels of physical
activity while patients in class III have any limitations at mild levels of
activity. Patients with symptoms at rest are categorized as class IV.
Hemodynamic Profiles
The impact of HF on circulatory physiology can be broadly categorized
into four groups based on the degree of impairment of cardiac output and
elevation of filling pressures (Fig. 5.1). Reduced cardiac output (cardiac
index, CI ≤2.2 L/min/m2) leads to impairment in end-organ perfusion.
Patients may complain of fatigue, dizziness, or diminished urine output.
On physical exam, extremities are cool due to low cardiac output and the
compensatory vasoconstriction of the capillary beds to maintain perfusion. This finding helps identify the “cold” patients in the low-output state.
Elevated filling pressures can cause hydrostatic pressure to increase
beyond the oncotic pressure, leading to extravasation of fluid into the
interstitial space. Fluid may be retained in the lungs causing dyspnea,
in the gut causing loss of appetite or nausea, and in the extremities
causing peripheral edema.
Most patients who present in acute HF exacerbation are “warm and
wet.” Despite elevated filling pressures and congestion, they are still
adequately perfused and can be treated with diuresis without hemodynamic support. “Cold and wet” patients are further decompensated.
They require inotropic support to maintain adequate blood pressures
and to perfuse the kidneys and permit effective diuresis. Some patients,
despite diuresis, may remain in a poor perfusion state due to underlying cardiac disease. These patients are “cold and dry” and may require
advanced therapies that will be described later.
PATHOPHYSIOLOGY
Frank-Starling Law
Under normal conditions, an increase in preload, or left ventricular
end-diastolic pressure (LVEDP), increases stroke volume, as described
by the Frank-Starling law (Fig. 5.2). In HF, the low cardiac output triggers an adaptive neurohormonal response that is designed to increase
preload and stroke volume. However, due to the depressed myocardial
contractility, the same increase in preload does not lead to increase in
stroke volume or cardiac output. The consequence is dysregulation of
an adaptive mechanism that leads to excessive filling pressures and fluid
retention. Treatment consists of augmenting stroke volume by reducing afterload and increasing myocardial contractility with an inotrope.
Diuresis can also reduce LVEDP, filling pressures, and congestive symptoms. Treatment of decompensated HF is discussed further in the section titled “Diagnosis and Management of Acute Decompensation.”
Adaptive Neurohormonal Response
Our understanding of HF has changed over the years. It is no longer
sufficient to consider morphologic characteristics or hemodynamic
profiles of this clinical syndrome. HF is a clinical syndrome marked by
sympathetic activation and neurohormonal dysregulation. The neurohormonal dysregulation and adaptive response are important targets
for HF management strategies.
In response to low cardiac output, the sympathetic nervous system
is triggered, releasing epinephrine and norepinephrine. The adrenalins
increase heart rate and cause ventricular relaxation. They also trigger
the G-coupled receptor pathways, increasing cyclic adenosine monophosphate (cAMP) production. Increased cAMP concentration leads
to calcium influx and augments myocardial contractility.
In the kidneys, the juxtaglomerular cells in afferent arterioles sense
decreased blood flow and in turn release renin. The consequent activation of the renin-angiotensin-aldosterone system (RAAS) is a cascade
CHAPTER 5 Heart Failure and Cardiomyopathy
Perfusion
Diurese
Congestion
Consider
Left ventricular end-diastolic pressure (mm Hg)
Stroke volume
45
TABLE 5.2 ACCF/AHA Stages and NYHA Functional Classification of HF
ACCF/AHA Stages NYHA Functional Classification
A Risk factors for HF without cardiomyopathy or HF symptoms None
B Cardiomyopathy without HF symptoms I No HF symptoms
C Cardiomyopathy with HF symptoms I
II
III
IV
D HF refractory to medical therapy IV HF symptoms at rest
ACCF, American College of Cardiology Foundation; AHA, American Heart Association; HF, heart failure; NYHA, New York Heart Association.
Data from Yancy CW, Jessup M, Bozkurt B, et al: 2013 ACCF/AHA guidelines 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 62:e147-e239, 2013.
No HF symptoms
Some HF symptoms with moderate activity
Any HF symptoms with mild activity
HF symptoms at rest
Dry
PCWP <22 mmHg
2
Warm
Cold
Fig. 5.1 Assessment of hemodynamic profiles in patients with heart
failure. CI, Cardiac index; PCWP, pulmonary capillary wedge pressure.
(Modified from Thibodeau JT, Drazner MH. The role of the clinical examination in patients with heart failure. JACC Hear Fail. 2019;6(7):544-551.
https://doi.org/10.1016/j.jchf.2018.04.005.)
Warm and dry
CI >2.2 L/min/m
2
Cold and dry
CI ≤2.2 L/min/m
Wet
PCWP ≥22 mmHg
Warm and wet
Cold and wet
inotrope
of enzyme activity that promotes end-organ perfusion by vasoconstriction, fluid retention at the level of the kidneys, and increased fluid
intake by stimulating thirst.
Over time, these mechanisms become dysregulated. The adrenalins augment chronotropy and inotropy, which increase wall stress
and myocardial oxygen consumption. Angiotensin II causes vasoconstriction that places the myocardium under higher afterload.
Initially, cardiac muscles become hypertrophied to compensate for the
workload; however, ventricles eventually dilate and lose contractility.
Aldosterone also exacerbates ventricular remodeling, leading to progressive decline in cardiac function and loss of myocytes with subsequent fibrosis in a process known as apoptosis.
Atrial natriuretic peptide and brain natriuretic peptide (BNP) are
counterregulatory hormones that are released in response to myocardial
stress. They promote natriuresis and arterial vasodilation. Neprilysin
degrades BNP and thereby inhibits the counterregulatory mechanism and inhibits natriuresis. This pathway is the target of novel drug
therapies described in the section titled “Guideline-directed Medical
Therapy.”
DIAGNOSIS AND MANAGEMENT OF ACUTE
DECOMPENSATION
Patients with HF frequently experience acute decompensation. Careful
history and exam, as well as laboratory and imaging findings can help
Normal
Inotropic
B
C
Adequate
Inadequate
Fig. 5.2 Frank-Starling curve. Pulmonary edema occurs when the left
ventricular end-diastolic pressure (LVEDP) is elevated such that hydrostatic pressures in pulmonary vasculature exceed oncotic pressures.
For most patients, this threshold is approximately LVEDP = 20 mm
Hg. Diuresis or venodilation reduces the filling pressures and can shift
patients along the same curve correlating with lower LVEDP. Inotropic agents or afterload reduction can improve the cardiac output and
improve stroke volume, shifting the pressure-volume curve upwards
and to the left, moving patients from point A to point B. Adding diuresis or venodilation can shift patients from point A to point C. Excessive diuresis or venodilation shifting from point A to point D may cause
excessive decline in LVEDP. While these patients may be at lower risk
of pulmonary edema, their stroke volume may be impaired and result in
inadequate cardiac output.
D
10 20
agent or
afterload
reduction
Depressed
A
contractility
Pulmonary edema
distinguish HF from other causes of dyspnea, such as chronic obstructive pulmonary disease (COPD) exacerbation or pneumonia.
History
Symptoms
HF is a clinical diagnosis. Thus, presenting symptoms, exam findings,
and patients’ response to HF treatments help establish the diagnosis.
Most patients with HF exacerbation present with dyspnea. Patients
may also experience orthopnea (shortness of breath while lying flat) or
paroxysmal nocturnal dyspnea or PND (waking up with shortness of
breath) due to redistribution of fluid from the periphery to the lungs.
Orthopnea and PND are specific for HF (specificity = 74% to 77%
for orthopnea and 80% to 84% for PND) and can help discriminate
among different etiologies for dyspnea.
Elevation of venous pressures (preload to the right ventricle) cause
symptoms of systemic venous congestion. Patients may complain of
46 SECTION II Cardiovascular Disease
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decreased appetite, nausea, and abdominal fullness from intestinal
edema of the gut. Transudation of fluid into the abdominal compartment may cause ascites and increased abdominal girth. Many patients
complain of leg swelling or inability to fit into their shoes. Asking
patients about sudden weight gain (e.g., 2-3 lb in a few days or 5 lb
in a week) can also help assess the degree of fluid accumulation and
identify targets for therapy.
Patients with inadequate cardiac output due to HF experience
fatigue, exercise intolerance, or presyncope. Reduced end-organ perfusion can lead to altered mental status and diminished urine output.
These symptoms are important clues to the hemodynamic profile of
the patient and are critical for determining their need for inotropic
support.
Precipitating Factors for Acute HF Exacerbation
Acute HF exacerbation may result from a new-onset primary cardiac
dysfunction or decompensation of known chronic HF due to noncardiac causes. Cardiac dysfunction causes of acute HF exacerbation
include acute myocardial infarction, other primary nonischemic cardiomyopathy, conduction disorders, valvular pathology, or pericardial
issues (see Table 5.1 for a comprehensive list).
The most common noncardiac causes of heart failure exacerbation are diet indiscretion (increased salt intake or alcohol consumption) and medication noncompliance. Other common causes include
infections (e.g., viral upper respiratory tract infection) or acute blood
loss anemia. High blood pressure can also increase afterload acutely,
increase filling pressures, and cause reduced cardiac output and/or
worsening congestion.
Additional Information for New-Onset Cardiomyopathy
Once heart failure exacerbation diagnosis is established, additional history elements can help determine cause of cardiomyopathy. Questions
should be focused on symptoms and risk factors of coronary artery
disease, given that myocardial infarction is the most common cause
of cardiomyopathy in the United States. Other helpful information
includes past medical history including valvular disease, arrhythmias,
autoimmune diseases, congenital heart disease, cancer, radiation, or
cardiotoxic therapy, such as anthracycline derivatives. Social history
should include duration and quantity of alcohol intake and cocaine
use. Symptoms suggestive of other systemic disorders affecting the
heart, such as neuropathy in amyloidosis, may be helpful and relevant
for treatment options. Family history may be important in cases such
as early-onset coronary artery disease, autoimmune disorders, congenital heart disease, and familial cardiomyopathies.
Exam Findings
Exam findings should be focused on signs of elevated filling pressures
and reduced cardiac output to establish the diagnosis of heart failure. Other exam maneuvers not reviewed here include those relevant
to myocardial ischemia, valvular disease, and arrhythmias that are
reviewed in Chapters 7, 8, and 9.
Edema, JVD, and HJR
Elevated filling pressures in the heart are detected by several physical
exam cues. Pulmonary auscultation may demonstrate rales, rhonchi,
or even wheezing. Edema may be found in the lower extremities, but
also in the abdomen in the form of ascites.
Jugular venous distension (JVD) is assessed with the patient situated at 30 to 45 degrees and breathing quietly. The vertical distance
between the sternal notch and top of the JVD meniscus is the jugular
venous height to which 5 cm should be added for true central venous
pressure (normal range = 5-9 cm H2O). Hepatojugular reflux (HJR) is
elevation of filling pressures by more than 3 cm H2O while compressing the right upper quadrant for at least 10 seconds. Valvular disease,
specifically tricuspid regurgitation, may falsely elevate the JVD meniscus and make these exam findings less reliable.
Cardiac Examination: S3 and S
The point of maximal impulse (PMI) may be displaced (below the fifth
intercostal space and lateral to the midclavicular line) suggestive of
cardiomegaly. On auscultation of the heart, a third heart sound (S3)
may be heard in early diastole. The sound is the result of blood passively traveling from the atrium into an already filled ventricle. This
is typically associated with left ventricular systolic dysfunction and
incomplete ejection of blood during systole. S4 is heard in late diastole
and results from the atrial kick pushing the remaining fluid into a stiffened ventricle. S4 suggests diastolic dysfunction.
4
Bendopnea
Bendopnea is a recently described simple stress maneuver that can be
used if the aforementioned exams are not helpful in discriminating
among the many causes of dyspnea. Patients are asked to bend forward while sitting in a chair for 30 seconds, which increases filling
pressures. Patients may develop dyspnea or “bendopnea,” particularly
if they have a low cardiac index. This maneuver has been associated
with increased 6-month mortality, composite end point of death, heart
failure–related admission, and need for advanced therapies.
Square Wave Response
Another stress maneuver to assess the left ventricular filling pressure is
the square wave response. This is particularly useful when the JVD and
HJR are limited due to body habitus or tricuspid regurgitation. The
blood pressure cuff is inflated to the point of hearing the first Korotkoff
sound. Then the patient is asked to Valsalva (i.e., bear down) in order
to reduce the preload and decrease pulmonary venous return to the
left ventricle. In normal patients, the Korotkoff sound disappears due
to a drop in blood pressure. In patients with pulmonary congestion,
the pulmonary intravascular volume maintains forward flow during
Valsalva, and the Korotkoff sound remains the same. The persistence
of Korotkoff sound, therefore, is a positive test and is suggestive of
elevated left ventricular pressures and pulmonary congestion.
Laboratory Data and Imaging
Patients who have symptoms and signs concerning for acute heart failure exacerbation should all receive an electrocardiogram (ECG) and
a chest radiograph. An ECG may show evidence of new ischemia or
old infarct suggesting MI as the potential cause for cardiomyopathy.
A chest radiograph may demonstrate signs of pulmonary edema, such
as Kerley B lines and pleural effusions (Fig. 5.3). The BNP is often elevated, although it is neither sensitive nor specific. In fact, BNP is most
useful for its negative predictive value. A low BNP (or NT-pro-BNP)
can exclude HF in patients with combined cardiopulmonary disease
who present acutely with dyspnea. The troponin may be elevated in
acute myocardial infarction or demand ischemia. Laboratory testing
should include a basic metabolic panel to establish baseline electrolytes and kidney function. The liver function test results help assess
the degree of congestion and cardiohepatic syndrome. The complete
blood count can give clues to the etiology, such as leukocytosis in the
setting of acute infection or anemia.
All patients with new-onset heart failure should have an echocardiogram. It may reveal wall motion abnormalities consistent with CAD,
valvular stenosis or regurgitation, or pericardial effusion. Ventricular
wall thickness and chamber sizes can also be assessed. Thickened ventricles may raise concerns for genetic hypertrophic cardiomyopathy,
CHAPTER 5 Heart Failure and Cardiomyopathy
A B
Fig. 5.3 (A) Posteroanterior chest radiograph demonstrating pulmonary edema. Notice the increased inter-
stitial markings, more prominent in central zones, and Kerley B lines, which are horizontal markings at the
lung periphery. There is also a prominent horizontal line in left lung, suggestive of fluid layering in the major
fissure. Both costovertebral angles are obscured, suggesting bilateral pulmonary effusion. (B) Lateral chest
radiograph demonstrating pulmonary edema. Fluid is layering in the lower lung zones suggestive of pulmonary effusion.
47
long-standing hypertension hypertrophic heart, or infiltrative disease
such as amyloidosis (Fig. 5.4). Newer techniques including strain
imaging can be used to evaluate for infiltrative disease as well as early
changes due to toxic chemotherapeutic agents.
Additional Testing to Determine Etiology
Appropriate patients with symptoms, signs, ECG, and/or troponin
results concerning for myocardial infarction causing heart failure exacerbation should undergo coronary angiography and revascularization.
Some patients presenting with new heart failure diagnosis have a history of coronary artery disease but do not have typical anginal symptoms. For these patients, the Surgical Treatment for Ischemic Heart
Failure (STITCH) trials demonstrated that myocardial viability assessment with nuclear stress testing does not, in fact, improve mortality.
However, the ACCF/AHA 2013 guidelines make weak recommendations to obtain noninvasive imaging such as nuclear stress test or stress
echocardiogram prior to proceeding with revascularization. Evidence
of ischemia and significant myocardial viability may be one of the factors to be considered for catheterization.
If the above work-up is negative, additional testing for nonischemic
cardiomyopathy can be pursued. A cardiac MRI can reveal specific patterns of enhancement that are indicative of infiltrative disorders (e.g.,
cardiac amyloidosis and sarcoidosis). Additional laboratory testing
may include thyroid function test, human immunodeficiency virus
(HIV) test, iron studies, and hepatitis C virus antibodies.
Prompt recognition and work-up for cardiac amyloidosis has
become more important as novel therapies have become available that are important to initiate early in the disease progression.
Features concerning for amyloidosis include low voltage on ECG, left
ventricular hypertrophy, and evidence of other organ manifestation
such as gastrointestinal symptoms (diarrhea, nausea), neuropathy,
and chronic kidney disease. Laboratory testing should include levels of serum and urine protein electrophoresis (SPEP and UPEP)
along with serum and/or urine immunofixation. Imaging techniques
include echocardiography, specifically strain imaging that tends to
spare the apex, and nuclear imaging called pyrophosphate (PYP)
scan. The latter is sensitive and specific for transthyretin, or wild-type
amyloidosis. Definitive diagnosis is achieved with direct visualization
of the amyloid deposits in tissue samples. Biopsy can be done on the
abdominal fat pad, cardiac muscle, rectal mucosa, salivary gland, and
liver.
Right heart catheterization is another diagnostic tool for assessment of acute HF exacerbation. The routine use of pulmonary artery
catheters (PACs) for patients with HF exacerbation has not been
shown to improve mortality, length of stay, or rehospitalization rates
(the Evaluation Study of Congestive Heart Failure and Pulmonary
Artery Catheterization Effectiveness, ESCAPE). The ACCF/AHA 2013
guidelines still recommend use of PACs with patients who do not
respond to standard therapies and when there is a degree of uncertainty regarding the patient’s volume status despite routine clinical
assessment. Right heart catheterization is also used to estimate cardiac
output, assess candidacy for advanced therapy, and perform cardiac
biopsy.
Acute Management
Diuresis
The mainstay treatment for acute HF exacerbation is intravenous (IV)
loop diuretics. Intravenous administration of diuretics should be equal
to or exceed the dose of home oral medications. Oral diuretics may
be less effective in this setting due to bowel edema which can impair
absorption via the gut. Diuresis should be targeted toward symptom
management, improvement in vital signs, resolution of acute kidney injury (AKI), change in weight, and net output of urine. Some
patients with prolonged diuretic use can develop resistance to loop
diuretics. These patients may benefit from thiazide administration to
block fluid reabsorption in the distal convoluted tubules. Patients who
do not respond to maximal diuretic regimen can be considered for
ultrafiltration.
48 SECTION II Cardiovascular Disease
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LV
S
LV
P
S
P
BA
LA
LV
Fig. 5.4 Examples of hypertrophic cardiomyopathy on (A) long axis view and (B) short axis view. The posterior
wall “P” and interventricular septum, “S” are markedly thickened. Examples of dilated cardiomyopathy on
(C) long axis view and (D) short axis view. The left ventricular cavity “LV” and left atrium “LA” are enlarged.
Afterload Reduction
Patients may be hypertensive in the setting of HF exacerbation. Acutely
lowering the blood pressure can quickly reduce the afterload, lower
ventricular filling pressures, and reduce the degree of pulmonary
vascular congestion. Patients in respiratory distress may experience
prompt relief of their symptoms with afterload reduction. Intravenous
therapy options for acute afterload reduction include nitroglycerin,
nitroprusside, and nesiritide.
Cardiogenic Shock Management
Some patients in acute HF exacerbation present in “cold” hemodynamic
profiles and have significantly reduced cardiac output. These patients
may require inotropic support for end-organ perfusion. The use of
inotropes can improve perfusion of kidneys and patients’ response to
diuresis. More information regarding the different types of inotropes
and their use is detailed in the section titled “Inotropic Support.”
Guideline-Directed Medical Therapy
In the current age, the goal in heart failure therapy is to not only control symptoms and slow progression of disease, but also to recover
some cardiac function. New pharmacotherapies have become available
DC
that not only improve functional status but lower mortality and reduce
hospitalizations. Thus, it is imperative to understand and follow
guideline-directed medical therapy (GDMT) for all patients with HF
(Fig. 5.5).
All patients with HF should be advised to make lifestyle modifications to reduce the risk of development or progression or cardiac
disease. Blood pressure control, weight loss, and management of diabetes can significantly reduce the risk of CAD and ventricular remodeling. Patients with any stage of heart failure, regardless of whether they
have symptoms, should be treated with ACE inhibitors or aldosterone
receptor II blockers (ARBs), as well as statins if there is evidence of
coronary artery disease or the atherosclerotic cardiovascular disease
(ASCVD) risk score is greater than 7.5%.
For patients with HFrEF stage C (i.e., patients with any symptoms),
several medications have been shown to reduce mortality and improve
quality of life. All patients should be treated with specific β-blockers
known to improve mortality in HFrEF patients, as well as a medication
for afterload reduction (ACE inhibitors, ARBs, or angiotensin receptor blocker–neprilysin inhibitors, i.e., ARNIs). The other therapies
described in the following sections have been proven effective for only
certain subpopulations.
CHAPTER 5 Heart Failure and Cardiomyopathy
At Risk for Heart Failure
Heart Failure
49
Stage A
At risk for HF but
without structural
heart disease or
symptoms of HF
e.g., Patients with:
• HTN
• Atherosclerotic
disease
• DM
• Obesity
• Metabolic
syndrome
Patients
• Using cardiotoxins
• With family history
of cardiomyopathy
Goals
• Heart healthy
lifestyle
• Prevent vascular,
coronary disease
• Prevent LV
structural
abnormalities
Drugs
• ACEI or ARB in
appropriate
patients for
vascular disease
or DM
• Statins as
appropriate
or
Therapy
Fig. 5.5 Clinical overview by HF stage A-D. ACEI, Angiotensin-converting enzyme inhibitor; AF, atrial fibril-
lation; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization
therapy; DM, diabetes mellitus; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart
failure; HRQOL, health-related quality of life; HTN, hypertension; ICD, implantable cardiac defibrillator; LV,
left ventricular; LVH, left ventricular hypertrophy; MCS, mechanical circulatory support. (Adapted from ACCF/
AHA 2013 Guidelines.)
Structural
heart
disease
Stage B
Structural heart
disease but without
signs or symptoms
of HF
e.g., Patients with:
• Previous MI
• LV remodeling
including
LVH and low EF
• Asymptomatic
valvular disease
Therapy Therapy Therapy
Goals
• Prevent HF
symptoms
• Prevent further
cardiac
remodeling
Drugs
• ACEI or ARB as
appropriate
• Beta blockers as
appropriate
In selected patients
• ICD
• Revascularization
or valvular surgery
as appropriate
Development
of symptoms
of HF
Goals
• Control symptoms
• Improve HRQOL
• Prevent
hospitalization
• Prevent mortality
Strategies
• Identification of
comorbidities
Treatment
• Diuresis to relieve
symptoms of
congestion
• Follow guideline
driven indications
for comorbidities,
e.g., HTN, AF,
CAD, DM
• Revascularization
or valvular surgery
as appropriate
e.g., Patients with:
• Known structural heart
disease and
• HF signs and symptoms
Stage C
Structural heart
disease with prior
or current
symptoms of HF
HFpEF HFrEF
Goals
• Control symptoms
• Patient education
• Prevent hospitalization
• Prevent mortality
Drugs for routine use
• Diuretics for fluid
retention
• ACEI or ARB
• Beta blockers
• Aldosterone antagonists
Drugs for use in
selected patients
• Hydralazine/isosorbide
dinitrate
• ACEI and ARB
• Digoxin
In selected patients
• CRT
• ICD
• Revascularization or
valvular surgery as
appropriate
Refractory
symptoms
of HF at rest,
despite GDMT
Stage D
Refractory HF
e.g., Patients with:
• Marked HF
symptoms at rest
• Recurrent
hospitalizations
despite GDMT
Therapy
Goals
• Control symptoms
• Improve HRQOL
• Reduce hospital
readmissions
• Establish patient’s
end-of-life goals
Options
• Advanced care
measures
• Heart transplant
• Chronic inotropes
• Temporary or
permanent MCS
• Experimental
surgery or drugs
• Palliative care and
hospice
• ICD deactivation
ACE Inhibitor, ARB, and ARNI
All patients with stage C HFrEF, regardless of symptom burden, should
be on an ACE inhibitor, an ARB, or an ARNI. By inhibiting RAAS, ACE
inhibitors and ARBs reduce afterload and inhibit fibrosis. Multiple trials from the 1980s to the early 2000s including CONSENSUS, SOLVD,
Val-HeFT, and CHARM demonstrated an improvement in mortality
(by 16% to 40%) and reduced hospitalizations for HF exacerbations in
patients treated with ACE inhibitors or ARBs.
The ARNI is a novel medication that combines the ARB, valsar-
tan, with a neprilysin inhibitor called sacubitril. Neprilysin is an
endopeptidase that breaks down vasoactive peptides such as BNP and
bradykinin. By inhibiting neprilysin, the sacubitril promotes the action
of the BNP, which increases diuresis. In the PARADIGM randomized
controlled trial (RCT) ARNIs were found to be superior to ACE inhibitors (number needed to treat, NNT = 21 for composite end point of
HF admissions or mortality). The PIONEER study also demonstrated
ARNIs could be safely started during hospitalization and readmission
due to HF exacerbations. The 2017 American College of Cardiology
and American Heart Association (ACC/AHA) updates to the guidelines recommend patients on ACE inhibitors or ARBs should be
50 SECTION II Cardiovascular Disease
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switched to ARNIs. Patients on ACE inhibitors should have a washout period of 36 hours after ACE inhibitors are discontinued to avoid
angioedema secondary to bradykinin accumulation.
The therapeutic potential of ACE inhibitors and ARBs for the
HFpEF patient population has been investigated by several RCTs,
including PEP-CHF, CHARM-preserved, and I-PRESERVE. These
studies unfortunately showed ACE inhibitors and ARBs do not significantly reduce cardiovascular mortality or heart failure exacerbations
in this patient group. The Prospective Comparison of ARNI with ARB
Global Outcomes in HFpEF (PARAGON-HF) also demonstrated no
significant risk reduction of mortality or HF-related hospitalizations
for ARNIs. Guidelines currently do not recommend initiation of ACE
inhibitors, ARBs, or ARNIs for HFpEF patients.
Beta-Blockers
The three types of β-blockers found to be effective in Stage C HFrEF are
bisoprolol, carvedilol, and metoprolol succinate. β-Blockers inhibit the
sympathetic nervous system, reduce myocardial work, improve endothelial integrity, and ultimately reduce ventricular remodeling. Numerous
studies—MERIT-HF, CAPRICORN, COPERNICUS, COMET, and
CIBIS-II—have demonstrated a significant reduction in mortality (31%
to 40%) and the composite end point of mortality and heart failure exacerbation admissions. The trials on HFpEF patients are small and inadequately powered, but many show a trend toward improving mortality.
Aldosterone Antagonist
Patients with stage C HFrEF, NYHA class II-IV already on β-blockers
and afterload reduction with an ACE inhibitor, ARB, or ARNI should
be started on aldosterone receptor antagonists assuming creatinine
clearance greater than 30 and normal potassium levels. The direct inhibition of aldosterone further reduces ventricular fibrosis and remodeling. The RALES trial showed a 30% reduction in all-cause mortality,
sudden cardiac death, and HF hospitalizations for patients with NYHA
class II-IV symptoms. EMPHASIS-HF also showed a 37% reduction in
the composite end point of death and HF readmissions.
Patients with HFpEF may also benefit from aldosterone receptor antagonists. The Treatment of Preserved Cardiac Function Heart
Failure with an Aldosterone Antagonist (TOPCAT) was an international, placebo-controlled, randomized study for patients with EF
45% or greater. The study showed a small effect size of spironolactone
reducing HF hospitalizations (12.0% vs. 14.2%). However, subsequent
analyses showed a significant regional variation, suggesting that North
American participants may have been more compliant with the medications and likely may have derived greater benefit.
Ivabradine
Patients with symptomatic HFrEF (stage C, NYHA class II-IV) with
high resting heart rate (≥70 beats per minute) despite treatment with
a high dose of β-blocker may benefit from the addition of ivabradine.
Ivabradine works by inhibiting If—the “funny channel”—at the sinus
node. The SHIFT trial demonstrated that patients in NYHA II-IV class
with EF 35% or less already on GDMT treated with ivabradine experienced a 5% absolute risk reduction in heart failure exacerbations and
2% absolute reduction in cardiovascular mortality.
Hydralazine and Nitrates
Vasodilators such as hydralazine and nitrates reduce afterload, myocardial work, and in theory, reduce ventricular remodeling. Their efficacy, however, has only been shown among African Americans with
HFrEF stage C and NYHA III-IV symptoms already on GDMT. For
patients with HFpEF, nitrates have been shown to improve exercise
tolerance but do not improve mortality (NEAT-HFpEF, 2015). The
ACC/AHA 2017 updates to the guidelines do not yet recommend vasodilators for HFpEF patients.
Digoxin
Digoxin increases myocardial contractility by inhibiting sodium-potassium exchange, which increases intracellular calcium. Digoxin is
associated with a decrease in HF hospitalizations, improvement in
quality of life, and increase in exercise tolerance. The DIG trials, however, showed no impact on mortality. Digoxin also has an unfavorable side effect profile. It can cause arrhythmias (ectopic, re-entrant
cardiac rhythms, and heart block), GI side effects (nausea, anorexia),
and neurologic side effects (visual effects, disorientation, confusion).
Patients who are elderly and have low body mass index or renal dysfunction are at higher risk. Many medications can increase the digoxin
level and increase the risk of toxicity (clarithromycin, erythromycin,
itraconazole, amiodarone, dronedarone, cyclosporine, propafenone,
verapamil, and quinidine). Given these risks and benefits, patients with
stage C HFrEF could benefit from digoxin.
Diuretics
For patients with chronic heart failure, diuretics are used to maintain
euvolemia and target symptom management. Loop diuretics are most
commonly used, but some patients develop resistance over time. Distal
convoluted tubules become hypertrophied and water becomes reabsorbed past the loop of Henle, reversing the effect of loop diuretics.
Small doses of thiazide and metolazone, which impact the distal nephrons, can significantly increase diuresis. Their use requires close and
careful monitoring of serum electrolytes and renal function.
Device Therapy
Cardiomyopathy confers an increased risk of ventricular arrhythmias
and sudden cardiac death (SCD). Patients with low EF of 35% or less
and NYHA class II-III symptoms should receive an implantable cardiac defibrillator (ICD) for primary prevention (Fig. 5.6). Numerous
trials—SCD-HeFT, CARE-HF, MADIT-CRT, and REVERSE—have
demonstrated reduction in SCDs that outweigh the risk of device-related complications for HFrEF patients.
Patients with ischemic cardiomyopathy are at higher risk for SCDs
due to the scar tissue that can be a nidus for ventricular arrhythmias.
Thus, patients with ischemic cardiomyopathy (EF ≤30%) should also
receive an ICD even if they do not have symptoms (NYHA class I). The
evidence behind device therapy for HFpEF patients, however, is less
clear. The DANISH trials demonstrated 3% mortality benefit but 1.5%
device-related complications.
Device therapy in the form of cardiac resynchronization therapy
(CRT), also termed “biventricular pacing,” has also been shown to
improve functional capacity, reduce HF rehospitalizations, and improve
all-cause mortality. Patients derive their benefit from improved contractility and increased forward flow due to ventricular synchrony.
Additional benefits include improvement in blood pressure, making it
possible to intensify therapy with ACE inhibitors, ARBs, and ARNIs.
Patients with HFrEF and a widened QRS of 150 ms or greater with a left
bundle branch block pattern should be considered for CRT implantation.
Management of Atrial Fibrillation
HF patients with atrial fibrillation (AF) are at higher risk of stroke, HF
exacerbations, and mortality. The AFFIRM trial demonstrated similar
outcomes between rate and rhythm control strategies; however, patients
with HFrEF were underrepresented. Theoretically, restoring sinus
rhythm allows preservation of the atrial kick and improvement in A-V
synchrony, which could reduce filling pressures and improve cardiac
output. Recently, CASTLE-AF demonstrated that patients with HFrEF
CHAPTER 5 Heart Failure and Cardiomyopathy
Patient with cardiomyopathy on GDMT for 3 mo or on GDMT and 40 d after MI, or
with implantation of pacing or defibrillation device for special indications
LVEF 35%
51
NYHA class I
• LVEF 30%
• QRS 150 ms
• LBBB pattern
• Ischemic
cardiomyopathy
• QRS 150 ms
• Non-LBBB pattern
Fig. 5.6 Recommendations for implanted cardiac defibrillator (ICDs) and cardiac resynchronization therapy (CRT)
depend on the ejection fraction (EF) and New York Heart Association (NYHA) functional class. Green indicates
class I recommendations (evidence or agreement that treatment is useful and effective), yellow indicates class
IIa recommendations (weight of evidence or opinion in favor of treatment), orange indicates IIb recommendations
(usefulness/efficacy is less well established), and red indicates class III recommendations (evidence or general
agreement that treatment is not useful/effect and in some cases may be harmful). GDMT, Guideline-directed medical therapy; LBBB, left bundle branch block; MI, myocardial infarction. (Adapted from ACCF/AHA 2013 guidelines.)
Evaluate general health status
Acceptable noncardiac health
Evaluate NYHA clinical status
NYHA class II
• LVEF 35%
• QRS 150 ms
• LBBB pattern
• Sinus rhythm
• LVEF 35%
• QRS 120–149 ms
• LBBB pattern
• Sinus rhythm
• LVEF 35%
• QRS 150 ms
• Non-LBBB pattern
• Sinus rhythm
• QRS 150 ms
• Non-LBBB pattern
NYHA class III and
Ambulatory class IV
• LVEF 35%
• QRS 150 ms
• LBBB pattern
• Sinus rhythm
• LVEF 35%
• QRS 120–149 ms
• LBBB pattern
• Sinus rhythm
• LVEF 35%
• QRS 150 ms
• Non-LBBB pattern
• Sinus rhythm
• LVEF 35%
• QRS 120–149 ms
• Non-LBBB pattern
• Sinus rhythm
Comorbidities and/or frailty
limit survival with good
functional capacity to 1 y
Special CRT
Indications
• Anticipated to require
frequent ventricular
pacing (40%)
• Atrial fibrillation, if
ventricular pacing is
required and rate
control will result in
almost 100%
ventricular pacing
with CRT
Continue GDMT without
implanted device
NYHA class II-IV experienced significant reduction in death (11.6%)
and heart failure exacerbation (15.2%) after catheter ablation to restore
sinus rhythm. Although not yet reflected in the guidelines, patients with
HFrEF who are symptomatic should be considered for AF ablation.
Invasive Hemodynamic Monitoring of Ambulatory Patients
For patients with recurrent heart failure exacerbations, ambulatory monitoring devices can allow for early detection of increase in filling pressures
and timely interventions. CardioMEMS is an implantable device placed
in the pulmonary artery that communicates real-time hemodynamics
measurements remotely to trained health care professionals. Multiple
RCTs have demonstrated their effectiveness. In COMPASS-HF patients
with NYHA class III monitored with CardioMEMS experienced a 36%
reduction of HF hospitalizations. Similarly, CHAMPION-HF demonstrated CardioMEMS could achieve up to 37% relative risk reduction in
HF exacerbations in the first 17 months. Device-related or systems-related complications were found to be exceedingly rare (freedom from
complications estimated to be 98.6%). Currently, the device is FDAapproved for patients with heart failure with NYHA class III symptoms
who have been hospitalized in the past year. The GUIDE-HF trial is an
ongoing investigation to determine the impact of CardioMEMS in the
NYHA class II and IV patient population and patients with elevated
BNP. Many ICDs now have the capacity to monitor physiologic parameters including heart rate variability and intrathoracic impedance, which
may be helpful for patient assessment and management.
Advanced Therapy
Patients with HFrEF stage D, who are refractory to medical therapy,
are challenging to manage. Appropriate patients with stage D symptoms despite optimal medical therapy should be referred to centers that
provide advanced circulatory support. Recent advances in mechanical support technology have made possible implantation of durable
pumps as destination therapy in patients ineligible for other therapy.
INTERMACS Profiles
Patients in HFrEF stage D can be further characterized with profiles developed by the Interagency Registry of Mechanically Assisted
Circulatory Support (INTERMACS). The INTERMACS profiles
52 SECTION II Cardiovascular Disease
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TABLE 5.3 INTERMACS Profiles
INTERMACS Profile Description Urgency of Interventions
1: Cardiogenic shock “Crash and burn”: critical cardiogenic shock despite increasing doses of
inotropes confirmed with rising lactate or acidosis
2: Progressive decline “Sliding on inotropes”: end-organ hypoperfusion evidenced by worsening renal
failure and inability to maintain euvolemia despite inotropic support
3: Stable but inotrope
dependent
4: Resting symptoms Symptoms of congestion occur at rest Within weeks to months
5: Exertion intolerant “Housebound”: comfortable at rest and basic activities of daily living but
6: Exertion limited “Walking wounded”: fatigues after a few minutes of activity. Could confirm cardiac
7: Advanced NYHA III Mild physical exertion is tolerable, but moderate activity causes symptoms Not yet indicated
INTERMACS, Interagency Registry of Mechanically Assisted Circulatory Support; NYHA, New York Heart Association.
Data from Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant.
2009;28(6):535-541.
“Dependent stability”: adequate end-organ perfusion and symptom control while
on inotropic support or temporary circulatory support device, but
unable to wean from inotropes
any other activity causes limiting symptoms
impairment with hemodynamic measures or cardiopulmonary stress test
Within hours
Within days
Within weeks to months
Depends upon nutrition, organ function, activity
Depends upon nutrition, organ function, activity
describe the range of symptoms from advanced NYHA class III (profile 7) to critical cardiogenic shock (profile 1) and can help assess the
urgency to evaluate for mechanical circulatory support or transplants
(Table 5.3). Patients in INTERMACS profiles 5 through 7 can be
monitored without immediate plan for advanced heart failure therapy. Patients with resting symptoms (profile 4) or receiving inotropic
support (profile 3) may need circulatory support sooner. Patients who
are “sliding on inotropes” (profile 2)—demonstrating poor end-organ
perfusion despite inotropic support—should be considered for immediate support within days and potentially transferred to a left ventricular assist device (LVAD) and transplant center. Patients in critical
cardiogenic shock (profile 1) take precedence in mechanical circulatory support or heart transplant, which may be needed within hours.
Inotropic Support
Patients who have persistent symptoms despite GDMT and volume
optimization, found to have elevated filling pressures and/or low cardiac output, may be appropriate candidates for ambulatory inotropic
support. Ambulatory inotropes can be used for either bridge to durable mechanical support or palliation of symptoms. The current evidence suggests that ambulatory inotropes compared to GDMT do not
improve mortality but may improve heart failure symptoms (improvement in NYHA class by 0.6 more than GDMT).
Inotropes commonly used include milrinone and dobutamine.
Milrinone inhibits phosphodiesterase and thereby causes vasodilation. Hemodynamics improve due to reduction in afterload, decrease
in pulmonary vascular resistance, and increase in cardiac contractility. Dobutamine is a sympathomimetic agent; it is an agonist for
α-1, β-1, and β-2 receptor. This leads to an increase in myocardial
contractility and stroke volume as well as decrease in total peripheral
resistance, or afterload. Adverse effects include arrhythmias and significant hypotension due to vasodilation. If patients are hypotensive,
norepinephrine (α-1 and β-1 receptor agonists) and dopamine (β-1
receptor agonist at medium doses and α-adrenergic receptor agonists
at high doses) are preferred agents because they can vasoconstrict
and increase blood pressure in addition to increasing myocardial
contractility.
Mechanical Circulatory Support
In the setting of acute cardiogenic shock, several options are available
for short-term mechanical support.
The intra-aortic balloon pump (IABP) is a counterpulsation pump
placed in the aorta and synchronized to native cardiac beats. It reduces
the afterload by deflating during systole and improves coronary perfusion pressure by inflating during diastole. The IABP-SHOCK II trials demonstrated no difference in 30-day mortality between patients
treated with inotropes alone and those with IABP. Compared to other
short-term mechanical supports, IABP provides only a small augmentation in cardiac output (500-600 mL/min/m2). Potential complications include limb ischemia, thrombosis, and vascular complications.
The Impella ventricular support system is an axial-flow pump that
pulls blood from the left ventricle through an inlet area near the tip
and expels blood from the catheter into the ascending aorta. There are
different sizes of Impella including 2.5 or CP, which are designed for
percutaneous peripheral insertion, as well as Impella 5.0 or LD, which
are designed for surgical insertion. Depending on the type of Impella,
it can provide 2.5 to 5 L/min/m2 of augmentation. The ISAR-SHOCK
and IMPRESS trials, however, have demonstrated no improvement in
mortality. In addition to limb ischemia and vascular complications,
the rotor in the pump can lyse red blood cells, causing significant
hemolytic anemia.
Venous arterial extracorporeal membrane oxygenation
(VA-ECMO) is a heart-lung bypass via venous and arterial cannulas
that pump the blood from the body through an external oxygenator.
Venous blood is drained from the right atrium and returned to the
distal arterial system providing near complete temporary circulation
support.
In addition to concerns of limb ischemia, hemolysis, and vascular
injury due to the cannulas, the north-south syndrome is a feared complication. In this syndrome, only the lower body receives oxygenated
blood through the arterial cannula, and the “north”—or the brain and
upper body—receives perfusion with the deoxygenated blood. This
may occur due to the position of the cannulas or the recovery of native
heart function. VA-ECMO is considered as a last resort and is available
at only select centers with the surgeons and infrastructure capabilities.
The advancement in durable mechanical circulatory support
devices has now made it possible for HF patients in cardiogenic shock
to be discharged and managed in ambulatory settings. Since the first
heart lung machine in 1953, the durable circulatory supports have
undergone significant transformation to reduce their size, noise, and
device-related complications (Table 5.4). In order to reduce pump
thrombosis, devices have evolved from axial-flow to centrifugal-flow.
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