Download Heart Failure with Preserved Ejection Fraction

Heart Failure with Preserved Ejection Fraction
Symptoms and signs of heart failure with preserved left ventricular ejection fraction (LVEF > 50%).
Presence of an underlying cause of heart failure with preserved ejection fraction (eg, comorbidities such as
hypertension, coronary artery disease, diabetes, chronic kidney disease; or underlying valvular heart
disease, restrictive cardiomyopathy, or specific myocardial diseases such as amyloidosis).
The diagnosis of diastolic heart failure, which is the most common cause of heart failure with preserved
ejection fraction, requires definite clinical evidence of heart failure, LVEF > 50%, and objective evidence of
LV diastolic dysfunction by echocardiography or cardiac catheterization.
General Considerations
Heart failure with preserved ejection fraction (HFpEF) is an increasingly common, debilitating syndrome of the
elderly, and it carries a high rate of morbidity and mortality. HFpEF accounts for nearly 50% of all
hospitalizations for heart failure, and two large epidemiologic studies have confirmed that patients with HFpEF
have a mortality rate that is nearly identical to heart failure with low ejection fraction.
HFpEF is the preferred term for patients with a normal ejection fraction who have the syndrome of heart
failure, because HFpEF highlights the fact that heart failure is a syndrome and not a distinct clinical or
pathophysiologic entity. Many investigators and experts have used the term "diastolic heart failure" for HFpEF
in the past. However, this term is not ideal for two main reasons. First, there is ample evidence that patients
with HFpEF have abnormalities in systolic function (as defined by tissue Doppler imaging), and many patients
with heart failure and low ejection fraction have abnormal diastolic function. Second, in the clinical setting,
patients with heart failure are currently classified into two categories: low ejection fraction (< 50%) and
preserved ejection fraction (> 50%). By calling HFpEF "diastolic heart failure," clinicians may not consider the
entire differential diagnosis of HFpEF (of which pure diastolic dysfunction is only one cause). HFpEF has also
previously been called "heart failure with preserved systolic function" or "heart failure with normal systolic
function." As stated above, it is now clear that many patients with HFpEF have abnormalities in systolic
function; therefore, HFpEF is a better term.
The most recent American Heart Association/American College of Cardiology (AHA/ACC) guidelines have used
the term "heart failure with normal ejection fraction." This term is also not ideal because there is considerable
controversy regarding the exact cutoff for a "normal" ejection fraction. Therefore, HFpEF is a slightly better
term and was used in the most recent Heart Failure Society of America guidelines on the management of
patients with heart failure. Finally, HFpEF has the advantage of being an easy mnemonic for patients to
remember. HFpEF sounds like "HUFF-PUFF," which helps patients understand this disease, in which dyspnea
and fatigue are two of the most common symptoms.
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Chinnaiyan KM et al. Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure. Am Heart J. 2007
Feb;153(2):189–200. [PMID: 17239676]
Heart Failure Society of America. Evaluation and management of patients with heart failure and preserved left ventricular ejection
fraction. J Card Fail. 2006 Feb;12(1):e80–5. [PMID: 16500575]
Hunt SA et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of
Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update
for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and
Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International
Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20;112(12):e154–235.
[PMID: 16160202]
Pathophysiology
Since HFpEF is heterogeneous, there is no single mechanism that can explain the pathophysiology of the
HFpEF syndrome. In some patients with HFpEF, such as those who have the signs and symptoms of heart
failure due to severe valvular disease or pericardial disease (ie, constrictive pericarditis), pathophysiology is
relatively straightforward and well-defined. However, in most patients with HFpEF, pathophysiologic
abnormalities cannot be ascribed to a single well-defined mechanism. Instead, these patients typically have
one or more of the following underlying pathophysiologic processes: (1) Diastolic dysfunction due to impaired
LV relaxation, increased LV diastolic stiffness, or both; (2) LV enlargement with increased intravascular volume,
which may be due to extracardiac factors such as renal insufficiency; (3) abnormal ventricular-arterial coupling
with increased ventricular systolic stiffness and increased arterial stiffness. In addition, left ventricular
hypertrophy and coronary artery disease are especially important in the pathophysiology of patients with
HFpEF.
A. Diastolic Dysfunction
Diastolic dysfunction occurs when the ventricle loses its normal ability to suction blood from the left atrium.
When the ventricle relaxes abnormally, filling is delayed and left atrial emptying is incomplete. An abnormally
stiff ventricle worsens the problem by also impeding left atrial emptying. The end result is abnormally high left
atrial and LV diastolic pressures. The LV loses its suction and instead of "pulling" blood from the left atrium
and pulmonary veins, it now relies heavily on left atrial contraction so that the LV can fill and distend
appropriately, and recoil in systole. This is one reason why atrial fibrillation is tolerated so poorly in patients
with advanced LV diastolic dysfunction with resultant elevation of left atrial pressure, pulmonary vascular
congestion, and poor cardiac output.
In patients with HFpEF who have substantial diastolic dysfunction as a cause of their symptoms, the pressure–
volume curve is shifted up and to the left In these patients, even small increases in central blood volume or
vascular (arterial or venous) tone can result in significant increases in left atrial volume and pulmonary venous
pressures. Patients with an upward and leftward shift in the LV diastolic pressure–volume relationship tend to
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have a high relative wall thickness (high LV mass/volume ratio), increased fibrosis and scar of the LV
myocardium due to ischemia, infarction, infiltrative disease, or radiation, and impaired active relaxation of the
myocardium (due to abnormal myocyte calcium homeostasis).
B. Left Ventricular Enlargement and Increased Intravascular Volume
Left ventricular enlargement is a key predictor of heart failure, regardless of ejection fraction. However,
patients with isolated diastolic heart failure are often thought to have small LV volumes. This apparent
discrepancy can be explained by the underlying cause of HFpEF and diastolic heart failure. It is likely that
patients with significant coronary disease or myocardial ischemia (even in the absence of epicardial coronary
disease) suffer from increased LV enlargement. In addition, many patients with LV enlargement have
increased intravascular volume due to comorbidities such as chronic kidney disease, anemia, and obesity.
Thus, LV enlargement and increased intravascular volume cause symptoms of HFpEF by a pathophysiologic
mechanism that is distinct from pure LV diastolic dysfunction.
C.Abnormal Ventricular-Arterial Coupling
Ventricular-arterial coupling describes the interaction between ventricular stiffness and central arterial
stiffness. In healthy patients, young and old, arterial and ventricular elastance (stiffness) are matched in order
to maintain optimal cardiac efficiency. However, with increasing age, ventricular stiffness is elevated and
results in decreased contractile reserve, thereby rendering elderly patients susceptible to heart failure, blood
pressure lability, and decreased exercise tolerance. Some patients with HFpEF appear to be particularly
susceptible to abnormal ventricular-arterial coupling. These patients have the age-related increases in
ventricular stiffness described above, but instead of matched ventricular and arterial stiffness, ventricular
stiffness rises out of proportion of arterial stiffness, which results in poor cardiac efficiency. These patients
tend to have high pulse pressure, and they tend to be most sensitive to diuretics whereby small changes in
blood volume result in large changes in blood pressure (either significantly hypertensive or hypotensive).
D. Left Ventricular Hypertrophy
Left ventricular hypertrophy contributes substantially to the pathophysiology of HFpEF and is an important risk
factor. Left ventricular hypertrophy limits coronary flow reserve, increases LV diastolic stiffness, and impairs
LV relaxation. Patients with LV hypertrophy suffer from an inability to adequately utilize the Frank-Starling
mechanism. Therefore, inadequate preload and chronotropic incompetence can lead to decreased cardiac
output, with resultant lightheadedness, dizziness, and exercise intolerance. Finally, because of increased LV
wall thickness, the subendocardium is especially vulnerable to ischemia in patients with and without epicardial
coronary disease due to decreased coronary blood flow during exercise. Subendocardial ischemia can cause
both systolic and diastolic dysfunction in these patients and further exacerbate HFpEF.
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E. Coronary Artery Disease
Approximately 40% of patients with HFpEF have concomitant coronary artery disease. In these patients,
coronary disease is often severe, involving multiple epicardial coronary arteries. Patients with prior myocardial
infarction, ongoing ischemia, or stable chronic coronary disease can all present with HFpEF. Myocardial
ischemia causes calcium sequestration in diastole, which results in impaired LV relaxation and increased LV
filling pressures. In areas of prior infarction or ongoing ischemia, regional systolic dysfunction and dysynchrony
can further exacerbate abnormal loading conditions and create a mixture of systolic and diastolic dysfunction.
Furthermore, patients with chronic coronary artery disease often have LV remodeling with resultant
ventricular enlargement, a known risk factor for increased mortality and heart failure, despite ejection
fraction. Preservation of ejection fraction occurs even in patients with prior infarction due to hypertrophy and
hyperdynamic function of non-infarcted areas.
Patients with coronary disease suffer from a vicious cycle of abnormalities that contribute to HFpEF. As noted
above, ischemia can cause impaired LV relaxation and increased LV filling pressures. Impaired LV relaxation in
turn can also adversely affect coronary blood flow and coronary flow reserve, which exacerbates ischemia.
Increased LV filling pressures results in extravascular compression of the small intramyocardial coronary
vessels, which can cause subendocardial ischemia. Increased LV end-diastolic pressure can also result in poor
epicardial coronary blood flow. Thus, ischemia begets worsening LV diastolic function, which begets more
ischemia.
Borlaug BA et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved
ejection fraction. Circulation. 2006 Nov 14;114(20):2138–47. [PMID: 17088459]
Kliger C et al. A clinical algorithm to differentiate heart failure with a normal ejection fraction by pathophysiologic mechanism. Am J
Geriatr Cardiol. 2006 Jan–Feb;15(1):50–7. [PMID: 16415647]
Maurer MS et al. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card
Fail. 2005 Apr;11(3):177–87. [PMID: 15812744]
Sohn DW et al. Hemodynamic effects of tachycardia in patients with relaxation abnormality: abnormal stroke volume response as an
overlooked mechanism of dyspnea associated with tachycardia in diastolic heart failure. J Am Soc Echocardiogr. 2007 Feb;20(2):171–
6. [PMID: 17275703]
Zile MR et al. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004
May 6;350(19):1953–9. [PMID: 15128895]
Clinical Findings
The first step in caring for a patient with HFpEF is to ensure the correct diagnosis (see section on Differential
Diagnosis below). Several criteria for the diagnosis of HFpEF exist. All require signs and symptoms of heart
failure and objective evidence of preserved ejection fraction ( 50%).
A. Risk Factors
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1. Age – Patients with HFpEF are almost universally elderly, and aging has several effects on cardiovascular
structure and function that are pertinent to HFpEF patients. Aging reduces the diastolic filling rate as a result
of prolonged relaxation, which results in left atrial overload and pulmonary venous hypertension. Arterial
stiffness increases with age, resulting in increased afterload and load-dependent diastolic dysfunction. In
addition, stiffening of the central arteries (which is especially common in women) leaves them less capable to
handle changes in blood volume, thereby increasing susceptibility to hypotension, lightheadedness, and
dizziness. Finally, aging reduces exercise capacity by increasing ventricular end-systolic chamber elastance
(stiffness), which results in decreased ability to augment contractility with exercise.
2. Hypertension – Hypertension is the most important risk factor for HFpEF and is present in most patients
with HFpEF. Hypertensive emergency with flash pulmonary edema is a common presentation of HFpEF.
Hypertension leads to LV hypertrophy, which causes impaired relaxation, poor coronary flow reserve, and
increased diastolic stiffness, all of which exacerbate HFpEF. Hypertension is also a potent risk factor for
epicardial coronary disease, which often complicates HFpEF. Ischemia causes both increased LV stiffness and
impaired LV relaxation. Many patients with HFpEF have symptoms of chronic angina. Alternatively, recurrent
heart failure may be an anginal equivalent in many patients with concomitant HFpEF and coronary disease.
3. Obstructive Sleep Apnea – Obstructive sleep apnea is a common comorbidity in patients with HFpEF, and it
can result in worsening LV hypertrophy and pulmonary hypertension. In addition, patients with HFpEF may
also have sleep-disordered breathing (such as Cheyne-Stokes respirations) due to their heart failure. Finally,
increased upper airway edema due to generalized heart failure may actually cause obstructive sleep apnea, a
finding that has been shown to improve with diuretic therapy. All of the above contribute to nocturnal
microarousals and hypoxia, which result in poor sleep quality, which in turn worsens daytime fatigue and
exercise intolerance. Therefore, there should be a low threshold to perform a sleep study on the patient with
HFpEF.
4. Other Clinically Important Risk Factors – Other clinically important risk factors for HFpEF include coronary
artery disease, diabetes, chronic kidney disease, obesity, atrial fibrillation, anemia, and chronic obstructive
pulmonary disease. All of these comorbidities have their own signs and symptoms that can complicate
presentations of HFpEF, and add to diagnostic, prognostic, and therapeutic complexities.
B. Symptoms and Signs
Symptoms and signs of HFpEF are identical to those in patients with heart failure with reduced ejection
fraction (systolic heart failure) and include dyspnea, fatigue, peripheral pitting edema, and jugular vein
distention (see Chapter 18). Exercise intolerance and acute decompensated heart failure are two common
presentations of HFpEF.
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1. Exercise Intolerance – Exercise intolerance is one of the main symptoms of HFpEF and one of the most
debilitating. In patients with HFpEF, there are many reasons for exercise intolerance, including the following:
Almost all patients with HFpEF have increased LV diastolic or left atrial pressures, or both. These pressure
increases are transmitted to the pulmonary veins, which can cause decreased lung compliance, which is
exacerbated by exercise.
Increased LV diastolic pressure during exercise can limit subendocardial blood flow at a time when there are
increased myocardial demands, thereby worsening diastolic function. Poor myocardial perfusion is even
worse in patients with LV hypertrophy, which is very common in patients with HFpEF.
Patients with HFpEF have an abnormal stroke volume response to tachycardia with blunted increase in cardiac
output with exercise. Inadequate cardiac output can increase lactate production and worsen muscle
fatigue.
2. Acutely Decompensated HFpEF – The most common factor in acute decompensation is uncontrolled,
severe hypertension. Other common clinical findings associated with acute decompensated HFpEF include
arrhythmias; noncompliance with medications or salt restriction, or both; acute coronary syndrome; renal
insufficiency; valvular regurgitation or stenosis; and infection (eg, pneumonia, urinary tract infection). It is
important to recognize the clinical factors associated with acute decompensation because preventing
hospitalization is one of the most important goals in patients with HFpEF.
C. Diagnostic Studies
The diagnosis of primary diastolic heart failure requires invasive or echo-Doppler evidence of diastolic
dysfunction (abnormal relaxation, filling, diastolic distensibility, or stiffness). With a comprehensive approach
to the assessment of diastolic function by echocardiography, the diagnosis of diastolic dysfunction can be
made reliably, as discussed below. Table 19–1 lists a standardized battery of diagnostic and prognostic tests
for patients being evaluated for HFpEF.
Table 19–1. Diagnostic Evaluation of Heart Failure with Preserved Ejection Fraction.
Cardiac imaging
Two-dimensional/M-mode echocardiography
Doppler echocardiography
Tissue Doppler imaging
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Contrast-enhanced cardiovascular MRI
Laboratory testing
Complete blood count with evaluation of anemia (if present)
Comprehensive chemistry panel (including liver function tests, albumin,
total protein)
Fasting glucose, hemoglobin A1c
Fasting lipid panel
B-type natriuretic peptide (or NT-proBNP)
Urine microalbuminuria
Serum and urine protein electrophoresis
Exercise testing
Cardiopulmonary exercise testing
Noninvasive evaluation of coronary artery disease (eg, stress
echocardiography)
Diastolic stress echocardiography
Cardiac catheterization
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Coronary angiography (if pretest probability is high or if stress test is
abnormal)
Invasive hemodynamic testing to confirm elevated LV diastolic pressure,
evaluate for constriction versus restriction, evaluate for pulmonary
hypertension, and dynamic testing (systemic or pulmonary vasodilator
challenge, fluid challenge)
Endomyocardial biopsy (in selected cases)
Other
Pulmonary function testing
Sleep study
1. Echocardiography – Echocardiography is the most important tool in diagnosing diastolic dysfunction and
evaluating for other etiologies of HFpEF, such as valvular, pericardial, and coronary disease. All patients with
possible or confirmed HFpEF should undergo comprehensive Doppler echocardiography with tissue Doppler
imaging. Besides assessment of diastolic function (see below), all patients should be evaluated for increased
LV mass and increased relative wall thickness (= [septal thickness + posterior wall thickness] / end-diastolic
dimension > 0.45). Assessment of pulmonary artery systolic pressure; right atrial pressure (from size and
collapsibility of the inferior vena cava); and right ventricular size, function, and thickness is important in
evaluation of pulmonary hypertension.
It is critically important to understand that no one abnormality on echocardiography can diagnose diastolic
dysfunction, and age must be factored into the diagnosis, since almost all parameters of diastolic function are
age-dependent. Only the proper combination of echocardiographic abnormalities can make the diagnosis of
diastolic dysfunction Figure 19–3 displays an algorithm for the diagnosis of diastolic dysfunction, which
requires comprehensive assessment of diastolic function, including mitral inflow, tissue Doppler imaging of
the mitral annulus, left atrial volume, and pulmonary venous flow. The first step in evaluating diastolic
function by echocardiography is to examine mitral inflow. In most patients, the ratio of early (E) to late (A)
mitral inflow velocities (E/A ratio) < 0.75 signifies impaired relaxation (grade I diastolic dysfunction), especially
if the patient is younger than 70 years and tissue Doppler E' is < 10 cm/s at the lateral annulus. In these
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patients, exercise stress echocardiography (see below) can help evaluate the functional significance of
impaired LV relaxation. If the E/A ratio is > 1.5 and early mitral deceleration time is < 150 ms in an elderly
patient, the diagnosis is grade III diastolic dysfunction. These patients universally should have an E' velocity <
10 cm/s at the lateral mitral annulus.
If the E/A ratio is 0.75–1.5 or if the E/A ratio is > 1.5 and early mitral deceleration time is > 150 ms, the
question of normal versus pseudonormal mitral inflow arises. In these cases, an E/E' ratio > 15 or E' velocity <
10 cm/s usually signifies pseudonormal mitral inflow (grade II diastolic dysfunction). In these patients, left
atrial volume index should be increased (> 28 mL/m2). Absence of left atrial enlargement should cause
reconsideration of the diagnosis of diastolic dysfunction. In patients who do not meet these criteria, further
evaluation with Valsalva maneuver, pulmonary venous flow, or flow propagation velocity can all be used to
help differentiate normal versus pseudonormal mitral inflow. Increased left atrial volume index and LV mass
index can both provide clues to the presence of diastolic dysfunction in these patients. Even with all of these
criteria for LV diastolic dysfunction, there is a subset of patients in whom diastolic function is indeterminate. In
addition, there are patients in whom diastolic function is difficult or impossible to assess noninvasively. These
patients include those with atrial fibrillation, tachycardia or tachyarrhythmia, moderate or greater mitral
regurgitation, mitral stenosis, mitral annuloplasty ring, mitral valve prosthesis, and mitral annular calcification.
It is important to note that although Doppler echocardiography is a powerful noninvasive tool for the
assessment of diastolic function, diastolic dysfunction is not synonymous with diastolic heart failure. Many
asymptomatic patients have abnormal diastolic function, but since they do not have signs and symptoms of
heart failure, they should not be diagnosed incorrectly with diastolic heart failure. In addition, all Doppler
echocardiographic variables for the assessment of diastolic function, except perhaps tissue Doppler E' velocity,
are extremely load sensitive, and therefore convey more information about preload and afterload than true
intrinsic diastolic stiffness. Therefore, it is always important to consider all clinical data, including clinical
history and physical examination when making the diagnosis of diastolic heart failure or HFpEF.
2. B-Type Natriuretic Peptide (BNP) – BNP may also have a role in the diagnosis of HFpEF. The Breathing Not
Properly Study showed that a BNP > 100 pg/mL had a high sensitivity and negative predictive value for the
diagnosis of HFpEF. Therefore, the diagnosis of HFpEF is unlikely in patients presenting to the emergency
department with dyspnea and a BNP < 100 pg/mL. However, there is considerable overlap of BNP values in
patients with and without HFpEF, especially in elderly women, since BNP increases with age, worsening renal
function, and in women. To complicate matters, morbid obesity has been associated with low BNP values,
which may be due to BNP clearance receptors on adipocytes. A gray-zone BNP of 100–500 pg/mL is common
and is of little help diagnostically. Furthermore, in HFpEF outpatients who are stable, BNP is less useful since it
may not be elevated. Therefore, BNP, like Doppler echocardiography findings, must be considered within the
context of the patient, and cannot be used as a stand-alone diagnostic test for HFpEF.
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3. Exercise Testing – Since exercise intolerance is a key symptom in HFpEF, exercise testing is extremely
valuable in these patients. Although many patients who are being evaluated for HFpEF may not be able to
withstand a Bruce protocol exercise test given their advanced age and multiple comorbidities, low-intensity
and bicycle stress protocols are very feasible. There are two simple exercise tests that are very helpful in
evaluating patients with HFpEF: cardiopulmonary exercise testing (CPET) and diastolic stress
echocardiography. Studies have shown that on CPET, patients with HFpEF have reduced exercise tolerance,
low peak workload, and low peak oxygen consumption (VO 2). Exertional dyspnea is prominent in HFpEF and
a VO 2 provides objective evidence of reduced exercise tolerance. Therefore, CPET can provide objective
evidence of exercise limitation and can confirm the diagnosis of HFpEF. In addition, CPET is useful in
differentiating cardiac from pulmonary components of dyspnea and decreased exercise tolerance. Often, CPET
is coupled with pulmonary function testing which also helps evaluate for pulmonary dysfunction, which is very
common in elderly patients with HFpEF.
Stress echocardiography for the evolution of diastolic function is a relatively new approach that aims to look
for increases in LV filling pressures with exercise. The diastolic evaluation stress can be combined with
traditional exercise stress echocardiography. Therefore, one test can diagnose coronary disease and exerciseinduced LV diastolic dysfunction. Patients are either tested with a treadmill or bicycle stress protocol. Baseline
images are obtained in the parasternal long axis, parasternal short axis, and apical two-chamber, fourchamber, and three-chamber (long-axis) views for assessment of wall motion. Baseline images should also
include Doppler assessment of early mitral inflow (E) and tissue Doppler imaging of the septal mitral annulus
(E'). At peak stress, wall motion analysis should come first, after which the patient should undergo repeat
assessment of mitral inflow and mitral annular velocities. In patients with exercise-induced diastolic
dysfunction, LV filling pressures remain elevated for several minutes, which is advantageous since the heart
rate must come down to below 100 bpm in order to prevent E and A (and E' and A') merging on mitral inflow
and tissue Doppler imaging, respectively. At peak exercise, an E/E' ratio > 13 (using E' at the septal annulus)
suggests exercise-induced increase in LV filling pressures and is diagnostic of exercise-induced diastolic
dysfunction.
4. Stress Testing for the Evaluation of Coronary Artery Disease – All patients with HFpEF should undergo
evaluation for coronary artery disease. Exercise stress echocardiography is ideal since patients can be
evaluated for the presence of coronary artery disease and exercise-induced diastolic dysfunction with one
test. However, adenosine or dipyridamole pharmacologic stress imaging is the test of choice in patients who
cannot exercise and in institutions where nuclear myocardial perfusion imaging is superior. Dobutamine stress
echocardiography can be performed, but in patients with significant LV hypertrophy, this test may have
reduced sensitivity for the detection of wall motion abnormalities.
5. Cardiac Catheterization – In patients with a high pretest probability for coronary artery disease and in
patients with abnormal results of stress testing, coronary angiography should be performed. LV diastolic
pressures should be measured in all patients to confirm the diagnosis of elevated LV pressures. Simultaneous
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right- and left-heart catheterization can be extremely valuable in the assessment of patients with HFpEF and is
often underutilized. Invasive assessment in the cardiac catheterization laboratory is currently the gold
standard for hemodynamic assessment, allows accurate assessment of cardiac output, and can be very helpful
in evaluating for restrictive cardiomyopathy, constrictive pericarditis, or pulmonary hypertension. In addition,
dynamic maneuvers such as fluid challenge, nitroprusside challenge, and pulmonary vasodilator testing (with
inhaled nitric oxide or intravenous adenosine) can be valuable in specific circumstances.
6. Cardiac Magnetic Resonance Imaging (MRI) – Cardiac MRI will likely play a key role in the assessment of
HFpEF in the future. Currently, cardiac MRI is the gold standard for assessment of LV volumes, left atrial
volume, and LV mass. In addition, cardiac MRI can evaluate for focal areas of fibrosis (hyperenhancement),
aortic enlargement and dissection (which is important since most patients with HFpEF have significant
hypertension), and pericardial thickness.
7. Endomyocardial Biopsy – In cases where cardiac MRI or echocardiography shows significant LV hypertrophy
but the patient has low voltage QRS complexes on electrocardiogram or the patient does not have a longstanding history of hypertension, it is important to perform endomyocardial biopsy to evaluate for a
potentially treatable cause of HFpEF.
Burgess MI et al. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular
filling pressure with exercise. J Am Coll Cardiol. 2006 May 2;47(9):1891–900. [PMID: 16682317]
Guazzi M et al. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol.
2005 Nov 15;46(10):1883–90. [PMID: 16286176]
Ha JW et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle
exercise Doppler echocardiography. J Am Soc Echocardiogr. 2005 Jan;18(1):63–8. [PMID: 15637491]
Kasner M et al. Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure
with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation. 2007 Aug 7;116(6):637–47.
[PMID: 17646587]
Kirkpatrick JN et al. Echocardiography in heart failure: applications, utility, and new horizons. J Am Coll Cardiol. 2007 Jul
31;50(5):381–96. [PMID: 17662389]
Lund LH et al. Peak VO2 in elderly patients with heart failure. Int J Cardiol. 2008 Apr 10;125(2):166–71. [PMID: 18067981]
Oh JK et al. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll
Cardiol. 2006 Feb 7;47(3):500–6. [PMID: 16458127]
Differential Diagnosis
When considering the differential diagnosis in a patient with HFpEF, it is important to first make sure that the
diagnosis of heart failure is correct. Mimickers of heart failure include pulmonary disease, obesity, and
anemia, all of which can cause shortness of breath and exercise intolerance. Edema, whether confined to the
lower extremity or more generalized, has a large differential diagnosis beyond heart failure, and includes
venous insufficiency or obstruction (eg, venous thrombosis), liver disease, renal disease (eg, nephrotic
syndrome), thyroid disease, and protein-losing enteropathies.
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Once the diagnosis of heart failure is confirmed, it is important to make sure that the LVEF has been accurately
measured, and that ejection fraction is truly preserved. A multiplanar imaging modality (most commonly twodimensional echocardiography) with quantitative measurement of ejection fraction (ie, biplane method of
discs) is essential for ensuring accurate quantitation of LV systolic function. An increasingly common group of
patients with HFpEF are those with a prior history of severe systolic dysfunction (often with LVEF < 25%) who
have recovered ejection fraction with medical or device therapies, but who continue to have mild-tomoderate symptoms of heart failure. These patients may have episodic or reversible LV systolic dysfunction,
such as patients with tachycardia-induced, alcoholic, viral, or tako-tsubo cardiomyopathy.
Once patients are categorized as true HFpEF, the differential diagnosis is broad. Table 19–2 lists the various
causes of HFpEF. It is also important to recognize common comorbidities in patients with HFpEF, which may
act in concert to cause signs and symptoms of heart failure. The most important comorbidities include
hypertension, diabetes, coronary artery disease, chronic kidney disease, obesity, anemia, and atrial fibrillation,
and it is common for multiple comorbidities to coexist in a single patient with HFpEF. Furthermore, many
patients have more than one of the aforementioned etiologies of HFpEF. For example, it is not uncommon for
an elderly patient to have HFpEF with hypertension, diabetes, chronic kidney disease, severe coronary artery
disease, and moderate mitral regurgitation.
Table 19–2. Etiologies of Heart Failure with Preserved Ejection Fraction.
HFpEF with abnormal diastolic function
Hypertensive heart disease
Coronary artery disease
Prior myocardial infarction,
Inducible myocardial ischemia, or
Severe chronic, stable multivessel coronary
disease
Restrictive cardiomyopathy
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Radiation-induced cardiac injury
Infiltrative
diseases
(amyloidosis,
sarcoidosis, hemochromatosis)
Metabolic storage diseases (eg, Fabry
disease)
Endocardial fibrosis
Primary diabetic cardiomyopathy (in the
absence of hypertension and coronary
disease)
Idiopathic
Hypertrophic cardiomyopathy
Obstructive
Nonobstructive
Other causes of HFpEF
Primary valvular heart disease
Aortic stenosis
Aortic regurgitation
Mitral stenosis
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Mitral regurgitation
Mimickers of obstructive valvular disease
(eg, left atrial myxoma, cor triatriatum)
Pericardial disease
Constrictive pericarditis
Cardiac tamponade
Primary right ventricular dysfunction
Pulmonary arterial hypertension
Right ventricular myocardial infarction
Arrhythmogenic right ventricular dysplasia
Congenital heart disease
High-output cardiac failure
Severe anemia
Thyrotoxicosis
Arteriovenous fistulae
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Prevention
HFpEF often represents the culmination of several underlying comorbidities such as hypertension, diabetes,
coronary artery disease, chronic kidney disease, and obesity. Therefore, it is imperative to aggressively treat
these risk factors in patients who may be at risk for HFpEF. Aggressive control of hypertension is probably the
most important factor in preventing HFpEF, and is a class I ACC/AHA recommendation for treatment and
prevention of HFpEF.
The VALsartan In Diastolic Dysfunction (VALIDD) trial showed that improvement in diastolic function is related
to decreases in blood pressure irrespective of type of antihypertensive therapy, and these findings underscore
the importance of aggressive blood pressure control in patients with hypertension in order to improve
diastolic function. Many studies have shown that lowering blood pressure reduces heart failure events, and
VALIDD adds to these studies by showing improvement in diastolic function with aggressive control of
hypertension.
Poor control of diabetes has been associated with increased incidence of heart failure (regardless of type of
heart failure). Although there is a tight association between poor glycemic control and incidence of heart
failure, it is unclear whether tight control of diabetes will reduce HFpEF. In the absence of randomized
controlled data, patients with diabetes should be treated aggressively with tight glycemic control, although
vigilance is needed to prevent hypoglycemic episodes. Tight glycemic control results in prevention of
microvascular complications, particularly diabetic nephropathy, which can result in fluid overload and heart
failure.
Treatment of ischemia is an attractive target for prevention of HFpEF. However, there is little data on whether
or not there is a benefit of revascularization. In the Coronary Artery Surgery Study (CASS) database, patients
with HFpEF had a higher mortality compared with those with preserved ejection fraction but no heart failure.
However, there were no differences in survival between patients with HFpEF who underwent surgical
revascularization and those who underwent medical therapy for multivessel coronary disease. Therefore,
patients with symptomatic angina and significant coronary disease should be treated with medications or
revascularization, or both, but whether doing so will prevent HFpEF remains to be seen.
Iribarren C et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001 Jun 5;103(22):2668–73.
[PMID: 11390335]
Solomon SD et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with
hypertension and diastolic dysfunction: a randomised trial. Lancet. 2007 Jun 23;369(9579):2079–87. [PMID: 17586303]
15
Treatment
A. Nonpharmacologic Therapy
All patients should keep a diary of daily weight and blood pressure. These two parameters are of extreme
importance in evaluating for underdiuresis and overdiuresis. When patients are educated about looking for
increased weight gain and increasing blood pressure, they can alert their health care provider in a timely
fashion in order to allow for intervention prior to progression of heart failure, which invariably leads to
hospitalization.
After undergoing cardiopulmonary exercise testing, all symptomatic patients should be referred for cardiac
rehabilitation for exercise training. Although there are no adequate clinical trials evaluating exercise therapy,
the downside of endurance training is minimal.
B. Pharmacologic Therapy
Treatment of HFpEF remains ill-defined. Unlike heart failure with reduced ejection fraction, there is a paucity
of randomized controlled trial data to guide treatment. To date, there are only very few randomized trials in
patients with HFpEF. These include the DIG trial, the CHARM-Preserved trial, and the Hong Kong Diastolic
Heart Failure Study.
In the DIG trial, digoxin did not decrease mortality, and although there was a trend toward decreased
hospitalization, there was also a trend toward increased unstable angina. Digoxin increases systolic energy
demand and adds to calcium overload in diastole and may be deleterious to patients with HFpEF; therefore, it
is generally not recommended. If digoxin is necessary for rate control in patients with HFpEF who have atrial
fibrillation, digoxin concentration should be kept at 0.5–0.9 ng/mL since higher concentrations were
associated with increased mortality in the DIG trial.
In the CHARM-Preserved trial of mostly younger male patients with ejection fraction > 40%, candesartan, an
angiotensin receptor blocker, was associated with a slight decrease in hospitalization but no difference in
mortality when compared with placebo.
In the Hong Kong Diastolic Heart Failure Study, 150 patients with HFpEF were randomized to diuretics,
diuretics plus irbesartan, or diuretics plus ramipril, and were monitored for 1 year.
Quality of life, symptoms, rate of recurrent hospitalization, and systolic and diastolic blood pressure were
similar in all three groups. However, the irbesartan and ramipril groups were better than diuretics alone in
reducing BNP and improving LV systolic and diastolic longitudinal LV function. Whether these changes
translate into improved long-term outcomes is unknown.
16
Since extensive randomized controlled trial data for HFpEF are not available, treatment of HFpEF relies on
extrapolation of therapies for heart failure with reduced ejection fraction, nonspecific relief of congestion, and
ameliorating the underlying disease processes and comorbidities. Table 19–3 lists the most important
treatment priorities for patients with HFpEF, as outlined below.
Table 19–3. Treatment of Heart Failure with Preserved Ejection Fraction.
Treat underlying causes and precipitating factors
Treat congestion and edema
Diuretics
Ultrafiltration or dialysis (when diuretics are insufficient)
Salt restriction
Vasodilator therapy
Aggressively treat hypertension
Use long-acting β-blockers (eg, carvedilol, metoprolol
succinate), ACE inhibitors or angiotensin receptor blockers,
and thiazide diuretics whenever possible
Avoid clonidine
Control heart rate and rhythm
Goal heart rate ~60 bpm (use caution in patients with
advanced diastolic dysfunction who require increased heart
rates to maintain cardiac output)
17
Maintain sinus rhythm (cardioversion, ablation)
Pacemaker therapy (when
atrioventricular synchrony
necessary)
to
maintain
Treat comorbidities
Myocardial ischemia (medications, revascularization)
Dyslipidemia (preferably with statins for pleiotropic benefit)
Anemia
Chronic kidney disease
Nonpharmacologic therapy
Instruct patients to keep diary of daily weight and blood
pressure
Prescribe exercise training (cardiac rehabilitation) in mild-tomoderate heart failure to improve functional status and
decrease symptoms
Treat obstructive sleep apnea, sleep-disordered breathing,
and nocturnal hypoxia
For symptomatic relief, the most important first step is to reduce the congestive state. Salt restriction and
vasodilator therapy (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, or
hydralazine/nitrates) make up the cornerstone of treatment. Diuretics and other forms of fluid removal (eg,
18
dialysis, ultrafiltration) are often needed, but as the acute congestive episode resolves, it is important to
minimize diuretic therapy, since overdiuresis activates a heightened neurohormonal response and aggravates
the cardiorenal syndrome.
From an electrophysiologic standpoint, it is important, whenever possible, to maintain atrial contraction and
atrioventricular synchrony. Therefore, patients with atrial fibrillation or atrial flutter should undergo
cardioversion or ablation. When necessary, patients should undergo pacemaker therapy to ensure
atrioventricular synchrony, although caution must be used to avoid prolonged right ventricular pacing since
this can ultimately lead to LV systolic dysfunction.
In most patients, it is ideal to promote bradycardia and avoid tachycardia. Tachycardia increases myocardial
oxygen demand and decreases coronary perfusion time, which promotes diastolic dysfunction due to ischemia
even in the absence of epicardial coronary disease. In addition, the time allotted for LV relaxation is decreased
and diastolic filling time is decreased when tachycardia is present. By inducing relative bradycardia (eg, heart
rate 50–60 bpm), coronary perfusion is optimized, and LV relaxation and diastolic filling time are both
increased. Patients who benefit most from this type of treatment are most likely those who have impaired LV
relaxation and prolonged early mitral inflow deceleration times. In patients with more severe, end-stage
HFpEF, such as severe restrictive cardiomyopathy, increased heart rate may be the most important factor
maintaining cardiac output, since stroke volume is often severely decreased. These patients invariably have a
very high early mitral inflow velocity and short deceleration time. Although tachycardia should be avoided,
heart rates of 80–90 bpm are often required in order to maintain adequate cardiac output. In these patients,
overzealous β-blockade or calcium channel blocker therapy can result in a precipitous decline in cardiac
output.
Most patients with HFpEF will benefit from rate control therapy with medications such as β-blockers and nondihydropyridine calcium channel blockers (verapamil, diltiazem). In the absence of adequate randomized
controlled trials, β-blockers with proven benefit in heart failure (metoprolol succinate, carvedilol, bisoprolol)
should be used as first-line agents in patients with HFpEF. A good rule of thumb to follow when choosing βblockers is that metoprolol succinate is a good agent in patients who have problems with rate control (eg,
atrial fibrillation) and those with low or normal blood pressure. In patients who have severe hypertension,
carvedilol is the agent of choice since it has potent antihypertensive effects due to its -adrenergic blockade
properties.
As stated above, all patients should be evaluated for myocardial ischemia, and when present, ischemia should
be treated aggressively with revascularization, β-blockers, nitrates, and dihydropyridine calcium channel
blockers. Hypertension should be treated aggressively with goal blood pressure < 130/80 mm Hg. Control of
hypertension is the only proven therapy for prevention of HFpEF, and therefore is essential in all patients.
HFpEF patients commonly have severe hypertension, and when they are referred, they may be taking four or
five or more antihypertensive medications. The number of medications should be kept to a minimum in order
19
to avoid the dangers of polypharmacy and adverse drug-drug interactions. In addition, minimizing medications
will often promote increased patient compliance. Patients with HFpEF and severe hypertension are often
taking medications such as clonidine and minoxidil, while other medications with proven cardiovascular
benefits, such as β-blockers and ACE inhibitors, are not titrated to maximum doses. Therefore, patients with
significant hypertension should ideally be treated with carvedilol, metoprolol succinate, or bisoprolol, and
maximum dose of an ACE inhibitor or angiotensin receptor blocker, unless contraindicated. Most patients will
also benefit from a thiazide diuretic such as hydrochlorothiazide or chlorthalidone. Routine use of more
potent thiazides, such as metolazone, should be avoided since these medications often exacerbate the
cardiorenal syndrome. In select patients with resistant hypertension, spironolactone may have substantial
antihypertensive effects, and in these cases hyperaldosteronism should be excluded.
In patients with severe, resistant hypertension who cannot be treated adequately with a combination of blockers, ACE inhibitors, and thiazide diuretics, the following steps should be taken: (1) ensure medication
compliance, (2) ensure euvolemia since fluid overload will exacerbate hypertension, and (3) look for causes of
secondary hypertension. Using these steps, most patients will have adequately controlled blood pressure with
two or three medications. In patients who need an additional agent, the combination of hydralazine and
nitrates is a good option given their beneficial effects in heart failure. If tolerated and not associated with
increased lower extremity edema, dihydropyridine calcium channel blockers may also be used to treat severe
hypertension. These agents are often useful in patients who have significant chronic kidney disease since they
may not be able to take ACE inhibitors, angiotensin receptor blockers, or aldosterone antagonists.
Besides beneficial antihypertensive effects, β-blockers, ACE inhibitors, and angiotensin receptor blockers
attenuate neurohormonal activation, which may be beneficial in HFpEF. In addition, ACE inhibitors,
angiotensin receptor blockers, and spironolactone may prevent fibrosis and may promote regression of LV
hypertrophy. Statins may have pleiotropic benefit in heart failure, and all HFpEF patients with dyslipidemia or
coronary risk factors should be treated with a statin. Interestingly, in a large study of Medicare beneficiaries
discharged with a primary diagnosis of heart failure and documentation of preserved ejection fraction, statins
were associated with increased survival irrespective of total cholesterol, coronary disease, diabetes,
hypertension, or age.
1. Caveats – Patients with HFpEF often live in a delicate balance between symptomatic congestion (due to
inadequate diuresis) and poor cardiac output (due to overdiuresis). The latter causes lightheadedness,
dizziness, fatigue, and worsening renal dysfunction due to decreased renal perfusion. Since patients with
HFpEF rely on increased LV filling pressures to maintain cardiac output, they tend to be very sensitive to
overdiuresis with small decreases in LV diastolic pressure resulting in large decreases in stroke volume.
Therefore, it is important to start low and go slow with diuretic therapy. Many patients typically require
frequent visits in order to find a diuretic regimen that results in optimal symptom control without
exacerbating the cardiorenal syndrome.
20
In patients with hypertrophic cardiomyopathy, verapamil may be beneficial, and therefore may be used as
first-line therapy before β-blockade. Alternatively, verapamil is contraindicated in amyloidosis. Thiazide
diuretics can exacerbate hyperglycemia and hyperuricemia, which are often present in elderly patients with
HFpEF. Positive inotropes should be avoided in general because they promote calcium influx into cardiac
myocytes, which worsens diastolic function. In addition, many of these patients have hypercontractile
ventricles with small LV volumes. Therefore, positive inotropes frequently cause cavity obliteration with
resultant obstruction of forward flow and decreased cardiac output. In patients with HFpEF who have non-ST
elevation acute coronary syndromes, mortality is increased and patients are often undertreated. Therefore, all
efforts should be made to treat this high-risk group (including an early invasive approach) using evidencebased guidelines.
Aside from treatment of hypertension, coronary disease, and atrial fibrillation (as listed above), it is important
to treat other underlying comorbidities such as diabetes, metabolic syndrome, obesity, chronic kidney disease,
and anemia. In addition, many patients with HFpEF have concomitant chronic obstructive pulmonary disease,
which should also be treated aggressively in order to improve symptoms of breathlessness.
2. Drugs to Avoid – In all patients with HFpEF, it is important to avoid polypharmacy at all costs since adverse
events increase and compliance decreases with increased numbers of medications. In addition, medications
should always be carefully scrutinized as causes of signs and symptoms of heart failure. For example, calcium
channel blockers and thiazolidinediones (eg, rosiglitazone, pioglitazone) can cause significant edema,
nonsteroidal antiinflammatory drugs can cause renal failure, and hydroxychloroquine (which is frequently
used in rheumatologic diseases such as systemic lupus erythematosus and rheumatoid arthritis) can cause a
restrictive cardiomyopathy. In the elderly cohort of patients with HFpEF, medications for Parkinson disease are
common, and these agents have been shown to cause valvular disease. Certain foods and herbal supplements
can also be deleterious in patients with HFpEF. Licorice can cause mineralocorticoid excess, ginseng interferes
with warfarin, and ginseng also falsely elevated digoxin levels. Treatment of gout is difficult since NSAIDs are
contraindicated in patients with HFpEF and colchicine is dangerous since many of these patients are elderly
and have abnormal kidney function. In these patients, corticosteroid injection directly into the involved joint, a
short pulse of oral corticosteroids, or gentle opioid therapy may be the best treatment options.
Ahmed A et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial.
Circulation. 2006 Aug 1;114(5):397–403. [PMID: 16864724]
Bennett KM et al. Heart failure with preserved left ventricular systolic function among patients with non-ST-segment elevation acute
coronary syndromes. Am J Cardiol. 2007 May 15;99(10):1351–6. [PMID: 17493458]
Martinez-Selles M. Treatment of heart failure with normal ejection fraction in patients with advanced chronic heart failure. Eur J
Heart Fail. 2007 Dec;9(12):1223. [PMID: 18006377]
Shah R et al. Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients >or=65 years of age
with heart failure and preserved left ventricular systolic function. Am J Cardiol. 2008 Jan 15;101(2):217–22. [PMID: 18178410]
Yip GW et al. The Hong Kong diastolic heart failure study: a randomized control trial of diuretics, irbesartan and ramipril on quality of
life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008
May;94(5):573–80. [PMID: 18208835]
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Yusuf S et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the
CHARM-Preserved Trial. Lancet. 2003 Sep 6;362(9386):777–81. [PMID: 13678871]
Prognosis
Once hospitalized for heart failure, patients with HFpEF have a high mortality. Five-year mortality is high, and
is similar to heart failure with reduced ejection fraction. Two large epidemiology studies of patients
hospitalized with HFpEF have shown that survival is only 30–40% after 5 years. Studies of outpatients with
HFpEF display a lower mortality, but one that is again similar to that of patients with heart failure and reduced
ejection fraction. Rates of hospitalization and readmission are similarly high in patients with HFpEF and heart
failure with reduced ejection fraction.
Despite the abundance of studies now showing a high rate of mortality in HFpEF, the cause of death remains
unclear. Predictors of death in patients hospitalized with HFpEF include increased age, male gender, increased
serum creatinine, decreased hemoglobin, decreased blood pressure, increased respiratory rate, and
hyponatremia. In addition, diabetes, peripheral arterial disease, cancer, dementia, and end-stage renal disease
requiring hemodialysis are all independent predictors of death in HFpEF. In the CHARM trial echocardiographic
substudy, evidence of moderate or greater diastolic dysfunction was strongly associated with adverse
outcomes. In the DIG trial, worsening heart failure and arrhythmias were the leading causes of death in all
heart failure patients, regardless of ejection fraction. However, noncardiovascular causes of death were more
frequent in patients with HFpEF, due to their advanced age. A retrospective analysis of the Duke Databank for
Cardiovascular Disease found that 8% of deaths in patients with HFpEF were due to sudden cardiac death. This
finding was mirrored in another study of 357 patients with HFpEF in whom 8% died due to sudden cardiac
death.
Cause of death in HFpEF is most likely multifactorial. Although some patients may die of heart failure and
pulmonary edema, most patients are not dying of LV pump failure, and many may be dying of arrhythmias or
sudden cardiac death. Even more may be dying of important age-related comorbidities such as cancer and
dementia. Until we learn more about cause of death in patients with HFpEF, it is important for health care
providers to understand the importance of comorbidities in the prognosis of these patients. Therefore,
although evaluation of treatment of HFpEF is extremely important, attention to comorbidities and a
multidisciplinary approach to patients with HFpEF will likely lead to the best possible outcome in these
patients.
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Electrophysiol. 2007 Dec;18(12):1231–5. [PMID: 17883404]
Bhatia RS et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul
20;355(3):260–9. [PMID: 16855266]
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Fonarow GC et al; OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments, and outcomes of patients with preserved
systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007 Aug 21;50(8):768–77.
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Owan TE et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul
20;355(3):251–9. [PMID: 16855265]
Persson H et al. Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence:results from the
CHARM Echocardiographic Substudy-CHARMES. J Am Coll Cardiol. 2007 Feb 13;49(6):687–94. [PMID: 17291934]
Shah SJ et al. Heart failure with preserved ejection fraction: treat now by treating comorbidities. JAMA. 2008;300:431–3. [PMID:
18647986]
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