Heart Failure with Preserved
Ejection Fraction
By Sheryl L. Chow, Pharm.D., FCCP, BCPS (AQ Cardiology)
Reviewed by Barry E. Bleske, Pharm.D., FCCP; Timothy Murray, Pharm.D., BCPS;
and Mary H. Parker, Pharm.D., BCPS (AQ Cardiology)
Learning Objectives (A)
or eject blood. Heart failure has a high incidence, with an
estimated 550,000 new cases diagnosed annually in the
United States, and high mortality, with one-half of these
patients likely to die within 5 years. Substantial increases
in the incidence and costs associated with this disease
have occurred; its sequelae: in 2010, $40 billion was spent
on health care related to HF, with about 300,000 deaths in
the United States (Roger 2011).
A large proportion of all patients with HF are now
defined as having heart failure with preserved ejection
fraction (HFpEF), also referred to as preserved HF, diastolic HF, or HF with preserved systolic function. These
patients will generally show classic signs and symptoms
of systolic HF in the presence of what is considered normal ejection fraction (EF) (i.e., 40%–65%) (Smith 2003;
Gaasch 1994). Despite the substantial risk of morbidity and mortality, effective treatment options are largely
empiric, given the lack of evidence to date. Current guidelines focus on treating comorbidities and improving signs
and symptoms of patients with HFpEF. Additional large
randomized controlled studies are needed in this patient
population to improve our current understanding of the
mechanisms, pathophysiology, and effective treatment
strategies to improve clinical outcomes.
1. Demonstrate the association between heart failure with
preserved ejection fraction (HFpEF) and survival.
2. Given a patient with heart failure (HF), recognize
HFpEF on the basis of clinical signs and symptoms,
physical examination, echocardiography, and radiographic findings.
3. Classify patients at high risk of hospitalization and
mortality through assessing risk factors, clinical presentation, and interpretation of biomarkers.
4. Distinguish the clinical presentation, diagnosis, and
treatment strategies of HFpEF from those of HF with
reduced ejection fraction.
5. Given a patient with HFpEF, develop an individualized
treatment plan based on current evidence.
6. Assess the potential role of future pharmacotherapies
for HFpEF.
Introduction (A)
Heart failure (HF) is a complex clinical syndrome that
can result from any cardiac structural or functional disorder that impairs the ability of the ventricle to fill with
Baseline Knowledge Statements
Readers of this chapter are presumed to be familiar with the following:
■■ Criteria for NYHA functional classification in patients with heart failure
■■ Pharmacologic management of patients with systolic heart failure as recommended by the American College of Cardiology/
American Heart Association and Heart Failure Society of America guidelines
Additional Readings
The following free resources are available for readers wishing additional background information on this topic.
■■ American College of Cardiology/American Heart Association Practice Guideline: 2009 Focused Update Incorporated
into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation
2009;119:e391-e479.
■■ Heart Failure Society of America. 2010 Comprehensive Heart Failure Practice Guideline.
■■ Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology.
ESC Guidelines for the Diagnosis of Acute and Chronic Heart Failure 2012. Eur Heart J 2012.
PSAP 2013 • Cardiology/Endocrinology
1
Heart Failure with Preserved Ejection Fraction
(HFrEF), an increase in preload or left ventricular end
diastolic pressure is produced as a result of a reduced contractility, EF, and ventricular compliance. In contrast,
HFpEF is associated with an increase in left ventricular diastolic pressure through abnormalities of diastolic
function, specifically related to impaired relaxation and
stiffness. Although both types of HF eventually produce
elevated filling pressures, the mechanisms associated
with each are quite distinct. Table 1-1 describes the various etiologies of HF; Table 1-2 compares characteristics of
HFpEF and HFrEF.
Abbreviations in This Chapter (A)
ACE
Angiotensin-converting enzyme
ARB
Angiotensin receptor blocker
CHARM-
Candesartan in Heart Failure:
Preserved Assessment of Reduction in Mortality
and Morbidity–Preserved study
EF
Ejection fraction
HF
Heart failure
HFpEF
Heart failure with preserved ejection
fraction
HFrEF
Heart failure with reduced ejection
fraction
I-PRESERVE Irbesartan in Heart Failure with
Preserved Ejection Fraction
LVEDP
Left ventricular end-diastolic pressure
LVEF
Left ventricular ejection fraction
NT-proBNP
N-terminal pro–B-type natriuretic
peptide
NYHA
New York Heart Association
RAAS
Renin-angiotensin-aldosterone system
Impaired Relaxation (C)
Impaired cardiomyocyte relaxation contributes to
diastolic dysfunction, which has been associated with
elevated filling pressures. The degree of myocardial relaxation can affect hemodynamic parameters by increasing
pulmonary vein pressure and left ventricular end-diastolic
pressure (LVEDP). However, this effect is also influenced
by heart rate. Although only minimal increases in pulmonary vein pressure and LVEDP are found at a heart
rate of 60 beats/minute, much larger elevations in both
are observed at a heart rate of 120 beats/minute because
of incomplete relaxation (Hay 2004). Therefore, both
impaired relaxation and heart rate can contribute to the
elevated filling pressures that produce the characteristic
clinical signs and symptoms of HF.
Prevalence of HFpEF (B)
The prevalence of HFpEF is high; an estimated 20%–60%
of patients with HF have relatively normal left ventricular
ejection fraction (LVEF). The exact prevalence is unknown
because of inconsistent assessment of EF and criteria used
to define HFpEF. However, in prospective studies, 50% of
patients with a diagnosis of HF have preserved EF. Patients
with HFpEF are generally older (73–79 years) and more
often are women who have hypertension.
Increased Diastolic Stiffness (C)
Left ventricular stiffness associated with HFpEF can be
caused by a variety of factors. Regulation of collagen can
produce hypertrophy of the extracellular matrix because
of an imbalance between collagen type I turnover. This
balance is regulated by matrix metalloproteinases,
enzymes that degrade collagen, and tissue inhibitors of
these enzymes. Intrinsic cardiomyocyte stiffness can
also contribute to left ventricular stiffness in HFpEF in
Pathophysiology (B)
Mechanisms of HFpEF (C)
The mechanisms of preserved and reduced HF differ
considerably. In heart failure with reduced ejection fraction
Table 1-1. Etiology of Heart Failure
HFrEF
HFpEF
Non-myocardial
High Output
Myocardial
Non-myocardia
High Output
Valvular disease
■■ AS
■■ AR
■■ MR
■■ MS
■■ Anemia
■■ AV fistula
Hypertension
CAD
DM
Dilated Cardiomyopathy
■■ Genetic
■■ Postpartum
■■ Viral
■■ Drug/radiation
Infiltrative myopathy
Valvular disease
■■ Anemia
■■ AS
■■ AV fistula
■■ AR
■■ MR
■■ MS
Pericardial constraint
■■ Constriction
■■ Tamponade
Myocardial
Hypertension
CAD
DM
Cardiomyopathy
■■ Genetic
■■ Postpartum
■■ Viral
■■ Drug/radiation
Infiltrative myopathy
AR = arrhythmia; AS = atherosclerosis; AV = arteriovenous; CAD = coronary artery disease; DM = diabetes mellitus; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MR = mitral regurgitation; MS = mitral stenosis.
Information from Heart Failure Society of America. Executive summary: HFSA 2010 comprehensive heart failure practice Guidelines. J
Card Fail 2010;16:475-539.
Heart Failure with Preserved Ejection Fraction
2
PSAP 2013 • Cardiology/Endocrinology
Table 1-2. Comparison of Pathophysiologic Characteristics Between HFpEF and HFrEF
Parameter
HFpEF
HFrEF
LVEF
Normal
Decreased
LVEDP
Increased
Increased
PCWP
Increased
Increased
Cardiac output
Normal or decreaseda
Normalb or decreased
Stroke volume
Normal or decreaseda
Decreased
Diastolic function
Impaired
Normal or impaired
BNP
Normal or increased
Increased
Neurohormonal activation
Increased
Increased
Left ventricular wall thickness
Increased
Decreased
Cardiac output and stroke volume may be normal at rest and abnormal with exercise.
With increased heart rate.
BNP = B-type natriuretic peptide; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction;
LVEF = left ventricular ejection fraction; LVEDP = left ventricular end-diastolic pressure; PCWP = pulmonary capillary wedge pressure.
Information from Barnes MM, Dorsch MP, Hummel SL, et al. Treatment of heart failure with preserved ejection fraction. Pharmacotherapy
2011;31:312-31.
a
b
conjunction with abnormalities formed in the cytoskeletal
protein titin (Borlaug 2011). Through one or more of these
pathophysiologic changes, an increased passive stiffness
of the left ventricle will result, leading to hemodynamic
abnormalities.
In patients with HFpEF, small changes in left ventricular volume are associated with relatively large changes
in ventricular diastolic pressure. Lack of ventricular compliance limits the Frank-Starling mechanism; therefore,
stroke volume does not substantially increase as filling
pressures rise (Zile 2004). An increase in diastolic stiffness often manifests as pulmonary edema because of the
high filling pressures required to achieve adequate venous
return.
such as left ventricular hypertrophy, endothelial dysfunction, and vascular and myocardial collagen deposition
(i.e., fibrosis) (Weber 2001).
Dysregulation of the autonomic system also occurs
in HF as a result of baroreflex response from inadequate
stroke volume. Activation of the sympathetic nervous system leads to progression of left ventricular remodeling,
reflected by rises in norepinephrine concentrations with
both types of HF (Kitzman 2002). Furthermore, sympathetic overactivity reduces downstream β-adrenergic
responsiveness, producing chronotropic incompetence
during exercise. Whether impaired heart rate response
is a compensatory mechanism to improve diastolic filling during exercise is unclear. However, similar to HFrEF,
patients with HFpEF are unable to adequately achieve
maximal exercise tolerance; as a result, they experience
dyspnea and fatigue (Barnes 2011; Phan 2010).
Neurohormones (C)
The renin-angiotensin-aldosterone system (RAAS) has
also been implicated in the pathophysiology and progression of both HFrEF and HFpEF (Barnes 2011). Although
neurohormonal activation of RAAS is well established
in systolic dysfunction, less is known about its contribution to diastolic dysfunction. However, hypertension, left
ventricular hypertrophy, myocardial fibrosis, and vascular dysfunction are all processes directly modulated by
RAAS that are closely associated with HFpEF (Massie
2008). Furthermore, the trophic effects of increased
angiotensin II activity are believed to impair the myocardium, leading to the development of HFpEF (Yamamoto
2000; Schunkert 1993). Aldosterone may also substantially contribute to the pathogenesis of HFpEF through
the mineralocorticoid receptor. The effects of aldosterone
activation itself can induce hypertension through sodiumwater retention and other associated HFpEF processes
PSAP 2013 • Cardiology/Endocrinology
Inflammation (C)
Inflammation is also believed to contribute to HF development and progression (Braunwald 2008). Circulating
levels of inflammatory markers such as C-reactive protein, interleukin-6, and tumor necrosis factor alpha, as
well as galectin-3 (a modulator of both inflammation and
fibrosis), are elevated in both types of HF and reportedly portend worse outcomes. The strong association
with HFpEF may be partly explained by inflammation
from common comorbidities such as hypertension and
chronic heart disease and by mechanisms related to elevated left ventricular filling pressures (De Boer 2011;
Kalogeropoulos 2010; Williams 2008). Despite recent
advances in knowledge, more data are needed to further
delineate the role of inflammation in HFpEF.
3
Heart Failure with Preserved Ejection Fraction
Prognosis (B)
Similar to patients with HFrEF, reports evaluating
patients with HFpEF estimate a 50% mortality rate at 5
years (Vasan 1999) with comparable morbidity and hospitalization. Re-hospitalizations for HF are estimated at 50%
by 6 months after discharge (Hunt 2009). Furthermore,
the functional status of patients with HFpEF is similar
to those of HFrEF. However, more patients with HFrEF
experience function-limiting dyspnea initially at baseline (odds ratio [OR] 0.62; 95% confidence interval [CI],
0.44–0.86; p=0.004), whereas patients with HFpEF are
functionally limited after 6 months (p=0.02). These data
and others indicate that in addition to significant overall
mortality in HFpEF, readmission and functional decline
after hospitalization contribute to substantial morbidity
(Smith 2003).
3.00–23.1, p<0.001), as was severe diastolic dysfunction
(i.e., advanced reduction in compliance or reversible/
fixed restrictive filling) (HR 10.17 [95% CI, 3.28–31.0],
p<0.001) (Redfield 2003).
Given that patients with HFpEF may not always present with clinical signs and symptoms of HF, diastolic
dysfunction can go unrecognized in the general population. However, even mild dysfunction is associated with a
marked increase in mortality. Therefore, it is important to
employ rigorous screening techniques in patients at risk of
developing HFpEF.
Cause of Death (C)
Although noncardiovascular deaths occur more
often in the HFpEF population than the HFrEF population, patients with HFpEF are still more likely to die of
cardiovascular causes than noncardiovascular causes.
Noncardiovascular mortality appears to be related to older
age and comorbidities such as diabetes and cerebrovascular accident. According to findings from the Irbesartan
in Heart Failure with Preserved Ejection Fraction
(I-PRESERVE) trial, an estimated 60% of patients with
HFpEF die of cardiovascular causes such as sudden cardiac death (26%), HF (14%), and myocardial infarction
(5%). Overall rates of cardiovascular death in this study
were lower than in patients with HFrEF from other randomized clinical studies (Zile 2010). Differences in rates
of cardiovascular death are likely caused by factors related
to structural and functional abnormalities. Patients with
HFpEF have diffuse and concentric remodeling, whereas
patients with HFrEF usually have focal areas of fibrosis.
Comorbidity Burden (C)
Patients with HFrEF and HFpEF experience similar
rates of overall mortality and hospitalization. However,
non-HF hospitalizations and noncardiovascular deaths
are higher for HFpEF, indicating that noncardiac
comorbidities influence outcomes to a greater degree in
these patients (Ather 2012). Hospitalized patients are generally older, obese, and anemic, and they are more likely
to have hypertension and atrial fibrillation than patients
with HFrEF (Owan 2006). Ambulatory patients with less
advanced HFpEF are also older, anemic, and hypertensive, and they tend to have higher prevalence of diabetes
mellitus, cerebrovascular accident, and chronic obstructive pulmonary disease than ambulatory patients with
reduced HF (Ather 2012).
In addition to the higher prevalence of comorbidities
associated with HFpEF, their impact on death may be different from reduced HF. For example, chronic obstructive
pulmonary disease is associated with increased mortality
in patients with HF; however, the risk of death is higher
with HFpEF than with HFrEF (Ather 2012). As such,
treatment of these comorbidities should be underscored
when managing patients with HFpEF.
Risk Factors and Lifestyle
Modifications (A)
Because HFpEF is closely associated with advanced age,
other age-related comorbidities are common. Diabetes,
hypertension, obesity, kidney failure, atrial fibrillation,
and anemia are observed more often with HFpEF than
with HFrEF (McMurray 2008). However, coronary
artery disease is more often associated with HFrEF (Ather
2012). Diabetes is a major risk factor for HFpEF, independently increasing the risk of 5-year mortality by 1.8 times
(Tribouilloy 2008). Furthermore, patients with diabetes are more likely to die of cardiovascular causes than
noncardiovascular causes. The risk factors for HFpEF
identified from epidemiologic studies can be categorized
as either modifiable (e.g., obesity, hypertension, diabetes,
coronary artery disease) or nonmodifiable (e.g., advanced
age, female sex) (Alagiakrishnan 2012). Patients at risk of
HFpEF should be counseled by appropriate caregivers on
how to reduce certain risk factors through lifestyle modifications (e.g., diet, exercise).
Diastolic Dysfunction and Survival (C)
A relationship between the severity of diastolic dysfunction and survival has been reported. However, only
one-half of those with diastolic dysfunction show clinical symptoms. Diastolic impairment measured by simple
mitral inflow patterns using Doppler echocardiography
was found to be associated with a 2-fold increase in allcause mortality and a 3-fold increase in cardiac death
(Bella 2002). Using data from more rigorous criteria
by Doppler measurements has shown a strong association between the severity of diastolic abnormalities and
survival. In a large cross-sectional survey, mild and moderate diastolic dysfunction (i.e., impaired relaxation with
moderate elevation of filling pressures) were predictive
of all-cause mortality (hazard ratio [HR]) 8.31; 95% CI,
Heart Failure with Preserved Ejection Fraction
4
PSAP 2013 • Cardiology/Endocrinology
Clinical Presentation and Diagnosis (A)
pulmonary artery systolic pressures (normal 15–30 mm
Hg) are common. Diastolic function is measured by two
major components of mitral flow: E wave (early passive
flow) and A wave (late flow with atrial kick). As diastolic
dysfunction worsens, left ventricular compliance becomes
further reduced, and left atrial pressure increases. These
changes are detected on echocardiography as high-velocity E wave with short deceleration time (less than 150
milliseconds) and low-velocity or absent A wave. The
left ventricular size is usually normal, with left ventricular hypertrophy observed in less than one-half of patients
with a diagnosis of HFpEF (Zile 2002a).
Biomarkers, to some extent, may help determine the
prognosis when used in combination with other diagnostic assessments to guide the clinical practitioner. Natriuretic
peptides are recommended to be used together with the
physical examination to diagnose acute HF (HFSA 2010a;
Hunt 2009; Dickstein 2008). In general, patients with both
types of HF will have elevated concentrations of natriuretic
peptides; however, median levels were higher with HFrEF
than with HFpEF in several studies (Bursi 2006; Maisel
The clinical presentation of HF may be indistinguishable between HFpEF and HFrEF (Table 1-3). Although
the presence of HF could be determined given the history,
physical examination, electrocardiography, or chest radiography, further testing by echocardiography is required.
Several criteria have been proposed for the diagnosis of
HFpEF, but a lack of consensus has prevented the establishment of a universally accepted approach. Practicing
cardiologists commonly diagnose HFpEF using signs
and symptoms of congestive HF as specified by the
Framingham criteria (McKee 1971) and defined by the
presence of an EF of 50% or greater on echocardiography
within 72 hours of presentation (Gandhi 2001). (These
criteria are loosely interpreted by those used in actual
clinical trials.) Differential diagnoses for HFpEF are presented in Box 1-1.
Echocardiography could also provide other findings
consistent with HFpEF that would serve to confirm the
diagnosis. Left atrial dilation is often a result of increased
left atrial pressures (normal 4–12 mm Hg), and elevated
Table 1-3. Comparative Incidence of Symptoms and
Signs in HFpEF vs. HFrEFa
Dyspnea on exertion
Paroxysmal nocturnal dyspnea
Orthopnea
Physical examination
Jugular venous distension
Rales
Displaced apical impulse
S3
S4
Hepatomegaly
Edema
Chest radiography
Cardiomegaly
Pulmonary venous hypertension
Incidence
in HFpEF
(%)
62–85
55
60
Incidence
in HFrEF
(%)
63–96
50
73
26–35
65–72
50
45
45
15
30–68
33–56
63–70
60
65
66
16
40–62
90
75
96
80
Box 1-1. Differential Diagnoses of HFpEF
■■
■■
■■
■■
■■
■■
■■
■■
■■
■■
■■
Atrial myxoma
Chronic pulmonary disease with right HF
Diastolic dysfunction of uncertain origin
Episodic or reversible LV systolic dysfunction
HF associated with high metabolic demand
Incorrect diagnosis of HF
Incorrect measurement of LVEF
Obesity
Pericardial constriction
Primary valvular disease
Pulmonary hypertension, associated with
pulmonary vascular disorders
■■ Restrictive cardiomyopathies (amyloidosis,
sarcoidosis, hemochromatosis)
■■ Severe hypertension, myocardial ischemia
HF = heart failure; HFpEF = heart failure with preserved ejection fraction; LV = left ventricular; LVEF = left ventricular
ejection fraction.
Information from Hunt SA, Abraham WT, Chin MH, et al.
2009 focused update incorporated into the ACC/AHA 2005
Guidelines for the Diagnosis and Management of Heart Failure
in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on
Practice Guidelines: developed in collaboration with the
International Society for Heart and Lung Transplantation.
Circulation 2009;119:e391-479.
HFpEF = heart failure with preserved ejection fraction; HFrEF
= heart failure with reduced ejection fraction.
a
HFpEF with EF > 50%; HFrEF with EF < 50%. Data
represented as percentage of patients in each group.
Information from Zile MR, Brutsaert DL. New concepts
in diastolic dysfunction and diastolic heart failure. Part I:
diagnosis, prognosis, and measurements of diastolic function.
Circulation 2002a;105:1387-93; and Fonarow GC, Stough WG,
Abraham WT, et al. Characteristics, treatments, and outcomes
of patients with preserved systolic function hospitalized for
heart failure. J Am Coll Cardiol 2007;50:768-77.
PSAP 2013 • Cardiology/Endocrinology
5
Heart Failure with Preserved Ejection Fraction
Diuretics (B)
Through different mechanisms, both patients with
HFrEF and patients with HFpEF experience symptoms of
volume overload caused by elevated left ventricular filling
pressures. Decreasing total fluid volume would therefore
reduce left ventricular pressure and improve patient symptoms. Diuretic therapy, which can reduce filling pressures,
has been reported to improve quality of life in patients
with HFpEF.
In one study, 150 patients with an LVEF greater than
45% were randomized to receive diuretics alone, diuretics plus irbesartan, or diuretics plus ramipril. At 52 weeks,
quality-of-life scores were improved from baseline in all
three groups (46%, 51%, and 50%, respectively; p<0.01
for all). Furosemide was used most often and improved
patient symptoms without additive benefit from irbesartan or ramipril (Yip 2008). Dosing of diuretics is extremely
important in these patients because small decreases in
diastolic volume can produce relatively large reductions
in blood pressure and cardiac output. Therefore, diuretics should be initiated at the lowest possible dose, together
with careful monitoring of blood pressure to avoid orthostatic hypotension (Zile 2002b).
In addition to symptomatic management, diuretic
therapy can be used to prevent HFpEF and HFrEF in
hypertensive patients. Medical management of hypertension in the elderly reduces HF risk by about 50% (Beckett
2008; Kostis 1997). The development of HFpEF after
treatment with chlorthalidone, a thiazide diuretic, was
compared with that of other antihypertensive drugs in
an analysis of the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT).
This trial enrolled more than 42,000 patients older than
55 years with hypertension and more than one risk factor for coronary artery disease. Chlorthalidone reduced
the risk of new-onset HFpEF better than amlodipine (HR
0.69; 95% CI, 0.53–0.91; p=0.009), lisinopril (HR 0.74;
95% CI, 0.56–0.97; p=0.032), or doxazosin (HR 0.53;
2003). Increased concentrations of N-terminal pro–B-type
natriuretic peptide (NT-proBNP) have also been reported
in HFpEF; however, natriuretic peptides tend to be less predictable in this population (Anand 2011). Attempts have
been made to use cut points (e.g., NT-proBNP greater
than 220 pg/mL, BNP greater than 200 pg/mL) for diagnosing HFpEF in the European guidelines (Paulus 2007).
One potential explanation for the unpredictability of these
biomarkers is that both BNP and NT-proBNP are influenced
by age and sex, as well as obesity and other comorbidities
closely associated with HFpEF (Packer 2011). Increased
concentrations may not directly reflect the severity of HF
or diastolic dysfunction, but rather, the comorbidities themselves. Therefore, natriuretic peptide concentrations are less
useful in this population.
Other researchers have studied biomarkers that specifically target adverse remodeling through myocardial
fibrosis, a key pathway in the pathophysiology of HFpEF.
Peripheral collagen markers (i.e., procollagen type I
amino-terminal peptide, procollagen type III aminoterminal peptide, osteopontin) were not independently
associated with clinically significant end points in this
population; however, the change in osteopontin over time
was predictive of all-cause mortality (Krum 2011). These
preliminary findings appear to support the role of fibrosis
in HFpEF. Future studies from I-PRESERVE will provide
more data about other profibrotic markers (i.e., galectin-3,
matrix metalloproteinase-9).
Treatment (A)
Clinical studies showing solid evidence in support of
medical management of HFpEF are lacking. Further studies
directed at the pathophysiology, biomarkers, and therapies
of pathways affecting the prevention and progression of diastolic dysfunction are needed. With this limitation, current
guidelines have mainly focused on improving patient symptoms and associated comorbidities. Table 1-4 summarizes
current treatment modalities.
Table 1-4. Treatment of HFpEF According to Clinical Signs and Pathologic Characteristics
Reduce LV volume and edema
Diuretics, reduce salt, nitrates
Treat systolic hypertension
Diuretics, β-blockers, CCBs, ACEIs, ARBs, MRAs
Reverse LVH
Antihypertensive agents (e.g., ARBs, diuretics)
Prevent ischemia
β-Blockers, CCBs, nitrates
Rate control or maintenance of sinus rhythmwith AF
β-Blockers, CCBs, amiodarone
Prevent fibrosis
ACEIs, ARBs, MRAs
Increase vascular compliance and myocardial relaxation
ACEIs
ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CCB = calcium channel
blocker (nondihydropyridines); HFpEF = heart failure with preserved ejection fraction; HR = heart rate; LVH = left ventricular hypertrophy;
MRA = mineralocorticoid receptor antagonist.
Heart Failure with Preserved Ejection Fraction
6
PSAP 2013 • Cardiology/Endocrinology
ACE Inhibitors/ARBs/Mineralocorticoid
Antagonists (B)
Activation of the RAAS is involved in the
pathophysiology and progression of HF. Drugs used to
target this pathway have shown significant reductions
in mortality and are considered cornerstone therapy
for chronic HF management in patients with HFrEF.
However, the evidence supporting angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) is less clear with HFpEF, despite a strong
association between RAAS and both left ventricular
hypertrophy and myocardial fibrosis.
Several clinical trials have investigated the effects of
RAAS inhibition in HFpEF and produced inconsistent
results (Table 1-5). The Perindopril in Elderly People
95% CI, 0.38–0.73; p<0.001) (Davis 2008). Furthermore,
risk of hospitalization was also reduced with chlorthalidone compared with amlodipine (HR 0.69;95% CI,
0.59-0.94; p=0.009), lisinopril (HR 0.74; 95% CI,
0.56-0.97; p=0.032), or doxazosin (HR 0.53; 95% CI,
0.38-0.73; p<0.001). These findings show the benefit of
thiazides in hypertension management and their importance for the potential to prevent hospitalizations or the
development of HFpEF. Thiazides are a reasonable choice
for the initial management of hypertension; however,
their preventive and therapeutic benefits must be carefully
weighed against the potential advantage of loop diuretics
for patients with kidney insufficiency or pulmonary congestion when greater diuretic effect is required.
Table 1-5. RAAS Inhibitor Trials of ACE Inhibitors and ARBs in Patients with Heart Failure with Preserved Ejection Fraction
Study/Treatment
Population
Duration
CHARM-Preserved
Candesartan vs. placebo
(Yusuf 2003)
3023 patients with
NYHA II–IV and
EF > 40%
36.6 months Reduction in CV death or admission to hospital for CHF
HR 0.86; 95% CI, 0.74–1.0; p=0.051 with fewer patients with
first CHF admissions (230 vs. 279, p=0.017)
Significant reductions in composite outcome of non-fatal MI
and nonfatal stroke (HR 0.86; 95% CI, 0.75–0.99; p=0.037)
I-PRESERVE
Irbesartan or placebo
(Massie 2008)
4128 patients at least
60 years of age with
NYHA class II–IV
and EF ≥45%
49.5 months No significant difference in death or hospitalization for cardiovascular cause
HR 0.95; 95% CI, 0.86–1.05; p=0.35
PEP-CHF
Perindopril or placebo
(Cleland 2006)
850 patients at least
70 years of age, wall
motion index < 1.4
(EF ≤ 40%) treated
with diuretics
2.1 years
Reduction in mortality
(HR 0.692; 95% CI, 0.474–1.010; p=0.055)
and significant reduction for heart failure hospitalizations
(HR 0.628; 95% CI, 0.408–0.966; p=0.033)
Improvements in functional class and 6-minute walk distance
with perindopril
Quinapril or placebo
(Zi 2003)
74 elderly patients
(mean age 78 years)
with NYHA II–III)
6 months
No differences in 6-minute walk distance or QOL scores
Losartan or placebo
(Warner 1999)
20 patients (mean age
64 years) with EF
> 50%
2 weeks
Exercise time increased to 12.3 minutes vs. 11.3 minutes at
baseline, and placebo (p<0.05 for both)
QOL improved with losartan vs. placebo (18 vs. 22, p<0.05)
38 weeks
No difference in blood pressure reduction or diastolic relaxation velocity between groups
Valsartan In Diastolic
198 patients with
Dysfunction (VALIDD)
hypertension with
Valsartan or placebo
LVEF > 50%
(Solomon 2007)
Significant Outcomes
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CHF = congestive heart failure; CV = cardiovascular; EF = ejection fraction; HR = heart rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York Heart Association;
QOL = quality of life; RAAS = renin-angiotensin-aldosterone system.
Information from Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-81; Massie BM, Carson PE, McMurray JJ, et al. Irbesartan
in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67; Cleland JGF, Tendera M, Adamus J, et al.
The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J 2006;27:2338-45; Zi M, Carmichael N, Lye
M. The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovasc Drugs Ther 2003;17:133-9; Warner
JG, Metzger C, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response
to exercise. J Am Coll Cardiol 1999;33:1567-72; and Solomon SD, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade
and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomized trial. Lancet
2007;369:2079-87.
PSAP 2013 • Cardiology/Endocrinology
7
Heart Failure with Preserved Ejection Fraction
with Chronic Heart Failure (PEP-CHF) study and
Candesartan in Heart Failure: Assessment of Reduction
in Mortality and Morbidity–Preserved study (CHARMPreserved) trials showed marginal to moderate decreases
in death or hospitalization for HF using RAAS antagonists;
however, I-PRESERVE resulted in no significant difference
in death or hospitalization. Important differences in trial
design and study enrollment may explain these disparities.
Because of inadequate enrollment and high attrition rates,
PEP-CHF was severely underpowered, limiting the interpretation of data. Furthermore, both CHARM-Preserved
and PEP-CHF enrolled patients with an EF greater than
40%—a less rigorous criterion for HFpEF by current standards. The I-PRESERVE trial was more appropriately
powered, used a stricter criteria (EF of 45% or greater), and
resulted in less impressive results. Despite conflicting findings from these three major trials, the totality of evidence
at present suggests that ACE inhibitors and ARBs are not
effective treatment for HFpEF.
Targeting the mineralocorticoid receptor using mineralocorticoid receptor antagonists (e.g., spironolactone,
eplerenone) may hold greater promise as an effective strategy for HFpEF. Aldosterone blockade been shown in
experimental studies to reduce myocardial fibrosis; decrease
inflammation; and improve vascular compliance, endothelial dysfunction, and myocardial perfusion. Aldosterone
may also improve collagen markers as well as clinical end
points in patients with HFpEF (Desai 2011; Daniel 2009;
Mak 2009; Roongsritong 2005; Mottram 2004).
Several small studies have investigated changes in echocardiographic parameters to detect clinical improvements
in diastolic function. One study showed that treatment
with eplerenone for 12 months produced no difference in
diastolic function parameters other than greater deceleration time compared with control (−82 milliseconds vs.
−7 milliseconds; p=0.032) and only modest functional
improvements (Mak 2009). Elevations in peripheral collagen marker procollagen type III amino-terminal peptide
were attenuated during treatment, suggesting a reduction in
collagen turnover; this supports eplerenone treatment as a
key mechanism in improving function in these patients.
Spironolactone has also shown benefit in symptomatic patients with HFpEF (Mottram 2004). Patients
randomized to 6 months of treatment showed significant
improvement of left ventricular long-axis systolic function,
as characterized by increases in long-axis strain rate, peak
systolic strain, and regional myocardial systolic function. Of
importance, these findings were independent of its antihypertensive effects, supporting a direct relationship between
aldosterone blockade and diastolic function.
The effects of spironolactone are currently being investigated in the Treatment of Preserved-Cardiac-Function
Heart Failure (TOPCAT) trial, a large randomized doubleblind study of more than 3000 patients with HFpEF (Desai
2011). This study enrolled patients who are symptomatic,
who are 50 years or older, whose LVEF is 45% or greater,
Heart Failure with Preserved Ejection Fraction
and who have been either hospitalized for HF within the
previous year or have elevated natriuretic peptides. The
primary composite end point is cardiovascular death, HF
hospitalization, or aborted cardiac arrest, although morbidity and quality of life, biomarkers, and echocardiographic
changes will be evaluated as well. The results of this study
should provide more conclusive data about the role of mineralocorticoid receptor antagonists in HFpEF.
β-Blockers (B)
β-Blockers have proven benefits in patients with systolic
dysfunction, but less is known about their use in patients
with HFpEF. Because tachycardia may unmask clinical
signs and symptoms of HF in patients with HFpEF, identifying therapy to reduce such symptoms seems warranted.
Rapid heart rates increase myocardial oxygen demand and
can promote ischemia. Furthermore, shortened diastole
as a result of HFpEF can either increase diastolic pressure
without improving diastolic volume or produce increased
heart rate and thereby worsen HF (Zile 2002a). Therefore,
β-blocker use could theoretically be used to maintain resting heart rates between 60 beats/minute and 70 beats/
minute to control tachycardia and promote diastolic filling,
which has potential to improve outcomes in patients with
HFpEF.
The theoretical potential of β-blockade to improve clinical outcomes in patients with HFpEF led to several trials
(Table 1-6). Benefit in patients with HFpEF was first investigated in a study of 158 patients with prior myocardial
infarction, LVEF of 40% or greater, and pulmonary congestion after treatment with diuretics and an ACE inhibitor
(Aronow 1997). Patients were randomized to either control group or propranolol. After 1 year of propranolol
treatment, LVEF was significantly increased from baseline,
and a greater reduction in left ventricular mass compared
with control was also observed. Furthermore, a 35% reduction in total deaths and 37% reduction in composite end
point of total mortality or nonfatal myocardial infarction
was observed after 32 months of propranolol therapy. A
major limitation to this study is that the criteria for LVEF
were less strict than in studies performed more recently.
Nevertheless, this study was the first to show a mortality
benefit with β-blockade in HFpEF.
In a more recent study, 113 symptomatic patients with
an LVEF of 45% or greater were randomized to either
carvedilol or placebo in addition to standard therapy, and
echocardiographic parameters were assessed (Bergstrom
2004). Although most parameters did not show a difference between groups, there was a significant improvement
in mitral flow E/A ratio with carvedilol driven by left ventricular relaxation. This effect was more pronounced with
higher heart rates, a condition that can produce an increase
in myocardial oxygen demand and a reduction in exercise
capacity in patients with HFpEF.
The potential effects of β-blockers on mortality were also
evaluated in elderly patients with HFpEF. The SENIORS
8
PSAP 2013 • Cardiology/Endocrinology
Table 1-6. Trials of β-Blockers in Patients with HFpEF
Duration
(months)
Study/Treatment
Population
Significant outcomes
Atenolol or
nebivolol
(Nodari 2003)
30 hypertensive patients
with NYHA II or III and
EF ≥ 50% with evidence of
diastolic function
6
Both atenolol and nebivolol significantly decreased improved
hemodynamic parameters (CI, SV, BP, HR) and E/A ratio at 6
months vs. baseline; however, nebivolol also reduced mPAP and
PCWP
BHAT trial
Propranolol or
control (no
propranolol)
(Aronow 1997)
158 patients at least 62 years
of age with NYHA class II
or III CHF and EF ≥ 40%
after diuretics and ACEI for
2 months
12
Greater increase in LVEF (p<0.0001) and reduction in LV mass
(p=0.0001) with propranolol vs. control at 1 year
Propranolol significantly reduced total mortality by 35%
(p=0.007) and combined end point of total mortality and
nonfatal MI by 37% (p=0.002)
Carvedilol or
standard
therapy
(Takeda 2004)
40 patients with mildmoderate HF and EF ≥
45%
12
Carvedilol improved NYHA functional class from 2.37 to 1.56
(p<0.01), BNP from 175 to 106 pg/mL (p<0.01), and exercise
capacity 4.75 to 5.68 METs (p<0.02). No significant changes
were observed with the conventional treatment
SWEDIC
Carvedilol or
placebo
(Bergstrom 2004)
113 symptomatic patients
with normal systolic LV
function and diastolic
dysfunction
6
No significant difference in mitral flow E/A ratio, deceleration
time, isovolumic relaxation time, and systolic/diastolic
pulmonary venous flow velocity during study
Significant improvement in E/A ratio at study end with carvedilol
vs. placebo (0.72–0.83 vs. 0.71–0.76, p<0.05)
SENIORS
Nebivolol in
impaired EF vs.
preserved HF
Substudy of 2111 patients
with symptomatic HF with
either reduced or reduced
EF (35 ≥ vs. < 35%)
21-month
follow-up
Nebivolol vs. placebo on all-cause mortality or cardiovascular
hospitalizations was 0.81 (95% CI, 0.63–1.04) in preserved EF
(p=0.720). No significance differences between nebivolol vs.
placebo between reduced vs. preserved EF groups
ACEI = angiotensin-converting enzyme inhibitor; BNP = B-type natriuretic peptide; CHF = congestive heart failure; CI = cardiac index; E/A
ratio = E/A wave = early passive flow/late flow with atrial kick; HFpEF = HF with preserved EF; HFrEF = HF with reduced EF; HR = heart
rate; LVEF = left ventricular ejection fraction; LVEDP = left ventricular end-diastolic pressure; MET = metabolic equivalent; MI = myocardial
infarction; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PCWP = pulmonary capillary wedge pressure;
SV = stroke volume.
Information from Nodari S, Metra M, Cas LD. Β-blocker treatment of patients with diastolic heart failure and arterial hypertension. A
prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail 2003;5:621-7; Aronow WS, Ahn C,
Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior
myocardial infarction, congestive heart failure, and left ventricular ejection fraction ≥ 40% treated with diuretics plus angiotensin-converting
enzyme inhibitors. Am J Cardiol 1997;80:207-9; Takeda Y, Fukutomi T, Suzuki S, et al. Effects of carvedilol on plasma b-type natriuretic
peptide concentration and symptoms in patients with heart failure and preserved ejection fraction. Am J Cardiol 2004;94:448-53; and
Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved
systolic function. Results of the Swedish Doppler-Echocardiographic Study (SWEDIC). Eur J Heart Fail 2004;6:453-61.
trial was a randomized, double-blind, placebo-controlled,
parallel-group trial evaluating the effect of nebivolol on
all-cause mortality or cardiovascular hospitalizations as a
composite end point. The substudy analyzed 752 elderly
patients (70 years and older) with an EF greater than 35%
(defined as HFpEF) versus 1359 patients with an EF of 35%
or less (defined as HFrEF) (van Veldhuisen 2009). The
mortality rates at 21 months were similar (31% in patients
with HFpEF, 34% in patients with HFrEF). Compared with
placebo, the hazard ratio for nebivolol in HFpEF was 0.81
(95% CI, 0.63–1.04; p=0.720). These findings suggest that
nebivolol showed similar effects on mortality in both categories of HF. However, the findings are limited given the
retrospective study design and less rigorous definition of
HFpEF.
PSAP 2013 • Cardiology/Endocrinology
Large randomized clinical trials are still needed to determine the benefit of β-blockers on outcomes in patients
with HFpEF. However, given the relationship between
heart rate and filling times, β-blockers may be a reasonable
option in patients with elevated heart rates and a comorbidity in which β-blocker therapy may be indicated (e.g.,
hypertension).
Calcium Channel Antagonists (B)
Nondihydropyridine calcium channel blockers (e.g.,
diltiazem, verapamil) have negative inotropic and chronotropic effects on the myocardium that can promote
relaxation and improve diastolic filling (Table 1-7). In a
small study, 20 symptomatic patients with HFpEF were
randomized to 5 weeks of verapamil or placebo; results
9
Heart Failure with Preserved Ejection Fraction
Table 1-7. Trials of Calcium Channel Blockers, Digoxin, Diuretics, and Mineralocorticoid Receptor Antagonists in Patients
with HFpEF
Study/Treatment
Population
Calcium Channel Antagonists
Verapamil or placebo 20 men with EF > 45%
(Setaro 1990)
and diastolic dysfunction
Verapamil or placebo
(Hung 2002)
Digoxin
DIG post hoc
analysis
(Ahmed 2006)
DIG substudy
analysis
(Meyer 2008)
Diuretics
Diuretics, irbesartan,
and ramipril
(Yip 2008)
Significant Outcomes
5-week crossover trial
Verapamil significantly improved exercise capacity from
baseline ([3.4–13.9 minutes] and filling rate [1.85–2.29
edv/second]; all p<0.05); placebo was not significantly
different
Verapamil improved CHF and LV diastolic function;
increased tolerance to exercise. Results showed a reduced
CHF score (from 5.6 to 3.5), decreased isovolumic
relaxation time (from 84 to 73 milliseconds), and
increased exercise time (from 7.4 to 8.3 minutes); p<0.05
for all) compared with baseline
15 elderly patients with
3-month crossover trial
NYHA II–III and diastolic (1-week washout)
dysfunction
5548 HFrEF and HFpEF
patients from the DIG
trial randomized to
digoxin or placebo
with serum digoxin
concentration at 1 month
916 pairs of patients with
systolic and diastolic HF
40-month median
follow-up
150 patients with HF, EF
> 45% randomized to one
of three treatment groups
QOL scores at 52 weeks,
echocardiographic
and hemodynamic
parameters at 1 year
QOL scores improved in all three groups. LVEF was
unchanged at 1 year, but diuretics with irbesartan or
ramipril improved LV function and lowered NT-proBNP
4 months
Spironolactone improved E/A ratio (0.71 to 0.84,
p=0.025) and deceleration time (285 to 230, p=0.035)
compared with baseline
Eplerenone did not significantly affect pro-collagen type
III and I aminoterminal peptides, MMP-2, IL-6 and IL-8,
and tumor necrosis factor-α at 6 months, but significantly
attenuated pro-collagen type III at 12 months (p=0.006)
Spironolactone improved myocardial function via
increased long-axis strain rate (−1.57 to −1.91 s-1,
p<0.01), peak systolic strain (−20.3% to −26.9%,
p<0.001), qualitative assessment of regional systolic
function (7.4 to 8.6 dB, p=0.08), and reduced posterior
wall thickness (p=0.04)
Mineralocorticoid Receptor Antagonists
Spironolactone or
30 elderly subjects
placebo
with isolated diastolic
(Roongsritong 2005) dysfunction
Eplerenone or
44 elderly patients with
control
HFpEF
(Mak 2009)
Spironolactone or
placebo
(Mottram 2004)
Duration
30 hypertensive patients
with dyspnea, EF > 50%,
and diastolic dysfunction
2-year follow-up
6 months
6 months
Serum digoxin concentration of 0.5–0.9 ng/mL
associated with lower all-cause mortality compared with
placebo (HR 0.77; 95% CI, 0.67–0.89; p<0.0001), CV
mortality (HR 0.83; 95% CI, 0.71–0.97; p=0.019), and
HF mortality (HR 0.63; 95% CI, 0.49–0.82; p<0.0001)
Type of HF (EF > 45%) did not influence results
Compared with placebo, digoxin decreased HF
hospitalization in HFrEF (HR 0.73; 95% CI, 0.54–0.97;
p=0.033) and HFpEF (HR 0.64; 95% CI, 0.45–0.90;
p=0.010)
CHF = congestive heart failure; CV = cardiovascular; E/A ratio = E/A wave = early passive flow/late flow with atrial kick; edv = end-diastolic
volume; EF = ejection fraction; HFpEF = heart failure with preserved ejective fraction; HFrEF = HF with reduced EF; HR = heart rate; IL = interleukin; LV = left ventricular; MMP = matrix metalloproteinase; mPAP = mean pulmonary artery pressure; NT-proBNP = N-terminal pro–B-type
natriuretic peptide; NYHA = New York Heart Association; QOL = quality of life.
Information from Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal left
ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981-6; Hung MJ, Cherng WJ, Kuo LT, et al.
Effect of verapamil in elderly patients with left ventricular diastolic dysfunction as a cause of congestive heart failure. Int J Clin Pract 2002;56:5762; Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis
of the DIG trial. Eur Heart J 2006;27:178-86; Meyer P, White M, Mujib M, et al. Digoxin and reduction of heart failure hospitalization in chronic
systolic and diastolic heart failure. Am J Cardiol 2008;102:1681-6; Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic heart failure study:
a randomized controlled 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;94:573-80; Roongsritong C, Sutthiwan P, Bradley J, et al. Spironolactone improves
diastolic function in the elderly. Clin Cardiol 2005;28:484-7; Mak GJ, Ledwidge MT, Watson CJ, et al. Natural history of markers of collagen
turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol 2009;54:1674-82; and Mottram PM, Haluska
B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation
2004;110:558-65.
Heart Failure with Preserved Ejection Fraction
10
PSAP 2013 • Cardiology/Endocrinology
showed a 33% relative improvement in exercise capacity and peak filling rate compared with baseline (Hung
2002). Functional improvement was further supported by
another small study showing increased exercise time and
reduced isovolumic relaxation time with verapamil after
3 months (Setaro 1990). Together, these results suggest
clinical benefit and therapeutic efficacy to improve exercise tolerance in elderly patients with HFpEF, although no
morbidity or mortality data exist on these agents. Given
their ability to reduce heart rate, they can also be used as
an alternative to β-blockers in patients with elevated heart
rates and comorbidities when calcium channel blockers
are indicated.
predispose the patient to other life-threatening arrhythmias. Both amiodarone and dronedarone are used to
treat tachyarrhythmias in patients with underlying structural heart disease, and both have been studied in this
population.
The effect of amiodarone in patients with HFpEF was
first examined in the Basel Antiarrhythmic Study of
Infarct Survival trial. There were 312 patients (primarily
men) with arrhythmias and HFpEF (mean EF 43%); 41%
of the study group had previous myocardial infarction.
Results from this study showed 5% mortality in the treatment group compared with 13% in the control group at 1
year, suggesting that amiodarone reduces sudden death in
this population (Burkart 1990). Long-term outcomes in
359 patients with HFpEF were further supported in a subanalysis of the Polish amiodarone trial, where this agent
reduced sudden cardiac death at 46 months when compared to placebo (Budaj 1996).
The effects of dronedarone on outcomes are discordant
with those of amiodarone. The Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of
standard therapy (PALLAS) investigated dronedarone
use in addition to standard therapy, but it was terminated
early because of safety concerns in this population. A total
of 3236 patients with atrial fibrillation were randomized
to dronedarone or placebo. Subgroup analysis showed an
increased risk of cardiovascular hospitalization or death,
which was significant for patients with HFrEF (HR 2.17;
95% CI, 1.15–4.070) and for patients with HFpEF (HR
1.61; 95% CI, 1.89–2.64) (Connolly 2011). Therefore,
dronedarone should be avoided in patients with permanent atrial fibrillation and HF.
These dissimilar effects between antiarrhythmics
in patients with HFpEF appear to support a role for
amiodarone but not for dronedarone. Although limited
data suggest potential benefit of amiodarone on sudden
cardiac death in select patients, there are profound safety
concerns with dronedarone use. Therefore, dronedarone
should be used selectively and with caution in all patients
with HF.
Digoxin (B)
In addition to its positive inotropic effects, digoxin
reduces the neurohormonal activation associated with
the pathophysiology of HF. By inhibiting the sodiumpotassium ATPase pump, this agent exerts a vagomimetic
effect not only on the heart but also the kidney, which
in turn reduces activity of the sympathetic nervous system and RAAS (Meyer 2008) Whether this improvement
by digoxin is regulated through baroreceptor function
remains to be established in HFpEF.
Clinical studies suggest the possible benefit of digoxin
for HFpEF. In a post hoc analysis of the Digitalis
Investigation Group (DIG) trial, 1687 patients with
both types of HF who received digoxin were compared
with 3861 patients who received placebo. The analysis
revealed that serum digoxin concentrations of 0.5–0.9
ng/mL reduced mortality in all patients with HF, including those with HFpEF, thereby expanding the potential
indication of digoxin to be used for both categories of HF.
Furthermore, this study supports standard digoxin therapeutic ranges (less than 0.9 ng/mL) for HFrEF as well as
HFpEF (Ahmed 2006).
In a more recent analysis of patients with HFpEF from
the DIG trial (Meyer 2008), there was a significant risk
reduction in the combined end point of HF hospitalization or HF mortality in those receiving digoxin at 2 years
(HR 0.69; 95% CI, 0.50–0.95; p=0.025), but this was
not significant at 3.2 years (HR 0.79; 95% CI, 0.60–1.03;
p=0.085). Improvements in the combined end point were
likely driven by improved HF hospitalization. Given the
high costs associated with hospitalization, these findings
support the role of digoxin in HFpEF. Despite these preliminary findings, further randomized clinical trials are
needed to establish the agent’s efficacy in HFpEF. At present, no guideline recommendations exist for using digoxin
to treat HFpEF. However, digoxin can be considered on
a case-by-case basis, especially in patients with frequent
hospitalizations for HFpEF.
Statins (B)
Statins produce a variety of effects independent of
low-density lipoprotein cholesterol reduction. Several of
these beneficial effects may prevent or improve HFpEF.
In addition to antifibrotic effects observed in experimental studies, statins can increase arterial distensibility and
reduce blood pressure in hypertensive patients. These
effects could decrease fibrosis, left ventricular mass,
and afterload in patients with HFpEF. Furthermore,
statins may reduce adverse remodeling after myocardial infarction and therefore may play a preventive role
in the development of diastolic dysfunction. Statins may
also have potential benefits on endothelial function and
inflammation (Fukuta 2005).
Amiodarone/Dronedarone (B)
Conditions such as myocardial infarction and HF
can increase the risk of sudden cardiac death and may
PSAP 2013 • Cardiology/Endocrinology
11
Heart Failure with Preserved Ejection Fraction
Statin mortality benefit in HFpEF was first reported in a
preliminary study that evaluated 137 patients with HF and
an EF of 50% or greater (Fukuta 2005). Patients receiving
statin therapy in addition to standard therapy had a lower
risk of death than those not receiving statins (relative risk
[RR] 0.22; 95% CI, 0.07–0.64; p=0.006). A retrospective study of 13,533 older patients with HFpEF reported
that statin therapy reduced 1- and 3-year mortality rates
(RR 0.69; 95% CI, 0.61–0.78) compared with nonstatin
therapy (RR 0.73; 95% CI, 0.68–0.79). These results were
still significant after adjusting for total cholesterol, coronary artery disease, diabetes mellitus, hypertension, and
age (Shah 2008). Other study data appear to support these
conclusions (Tehrani 2010).
According to current data and experimental studies,
statins appear to show benefits in patients with HFpEF.
Further prospective randomized studies are warranted to
determine whether statins should be standard therapy for
treating patients with HFpEF.
by improving left ventricular mass, diastolic function, and
left ventricular remodeling (Little 2005; Thohan 2005).
Another novel product specifically targeting the HFpEF
population was recently evaluated in the PARAMOUNT
trial (Prospective comparison of ARNI and ARB on
Management Of heart failure with preserved ejection fraction), a randomized, parallel-group, double-blind trial of
149 patients comparing LCZ696 versus valsartan alone.
The LCZ696 is a combination of valsartan and AH4377,
a neprilysin inhibitor that inhibits natriuretic peptide and
angiotensin degradation. Through the accumulation of
ANP (atrial natriuretic peptide), BNP, and CNP (C-type
natriuretic peptide), cyclic guanosine monophosphate is
attenuated, producing vasodilation and modest improvements in structural cardiac abnormalities. At 12 weeks,
systolic blood pressure and NT-proBNP were significantly
reduced in patients receiving LCZ696 compared with valsartan (9.3 vs. 2.9 mm Hg, p=0.001; and 605 vs. 835 pg/
mL, p=0.005, respectively). Furthermore, left atrial size
was reduced at 36 weeks, suggesting that LCZ696 lowers
the risk of associated HF events (Solomon 2012). These
surrogate markers suggest a potential benefit for patients
with HFpEF, but larger prospective studies are needed to
determine whether LCZ696 provides significant benefit
on clinical outcomes.
Future Therapies (B)
Several drugs have been investigated in experimental
studies and preclinical trials. Sildenafil reduces chamber size, pressure-induced ventricular hypertrophy, and
fibrosis (Westermann 2009; Takimoto 2005). Ivabradine
improves diastolic left ventricular function, reduces
hypoxia and remodeling, and increases nitric oxide
bioavailability through heart rate reduction in rats (Fang
2012). Ivabradine is currently approved for HF in Europe,
but clinical studies have exclusively focused on HFrEF.
As an inhibitor of late sodium current in cardiac myocytes, ranolazine could reduce intracellular calcium,
leading to improved myocardial relaxation. A small, randomized, prospective single-center trial is enrolling
patients to determine whether ranolazine can provide
clinical benefit in patients with HFpEF (Jacobshagen
2011).
Advanced glycation end-products are formed through
proteins and sugars to produce excessive crosslinks in the
myocardium and vasculature. These changes can lead to
diastolic dysfunction. Alagebrium, an advanced glycation
end-product crosslink breaker, was studied in patients
with HFpEF and showed promising preliminary results
Guideline-Based Assessment and Treatment Plan (B)
Several papers discuss the theoretical potential of
standard HF drugs in the treatment of HFpEF, but clinical evidence supporting efficacy is currently lacking.
Therefore, guidelines from the American College of
Cardiology/American Heart Association (Jessup 2009;
Hunt 2005), Heart Failure Society of America (HFSA
2010a), and European Society of Cardiology (McMurray
2012) focus on the diagnosis of HFpEF and recommend
empiric strategies for relieving signs and symptoms of HF
and treating associated comorbidities (Table 1-8).
In addition to blood pressure monitoring (goal less
than 130/80 mm Hg) and a low-sodium diet (2–3 g/
day), the use of a thiazide and/or loop diuretic as needed
is recommended for patients with clinical evidence of
hypervolemia and congestion. Because these patients are
generally more sensitive to diuresis, blood pressure and
kidney function should be carefully monitored. An ACE
Table 1-8. ACC/AHA Guidelines for the Treatment of HFpEF
ACC/AHA Guidelines Class 1 Recommendations
Treatment Modalities
Control blood pressure < 130/80 mm Hg
No specified antihypertensive agent
Prevent tachycardia or rate control in AF
Digoxin, BBs, CCBs, amiodarone
Reduce central blood volume
Low-salt diet, diuretics, nitrates
ACC/AHA = American College of Cardiology/American Heart Association; AF = atrial fibrillation; BB = β-blocker; CCB = calcium channel
blocker; HFpEF = heart failure with preserved ejection fraction.
Heart Failure with Preserved Ejection Fraction
12
PSAP 2013 • Cardiology/Endocrinology
inhibitor should also be considered, especially in symptomatic patients with HFpEF who have atherosclerotic
cardiovascular disease or diabetes and one additional risk
factor (e.g., hypertension). An ARB should be considered
in patients who cannot tolerate ACE inhibitors.
β-Blockers are recommended for patients with prior
myocardial infarction, history of hypertension, or atrial
fibrillation requiring ventricular rate control. β-Blockers
may be an even stronger consideration in treating
comorbidities such as hypertension in patients with elevated heart rates. For patients in whom calcium channel
blockers are indicated (e.g., symptomatic angina or hypertension), nondihydropyridine calcium channel blockers
(e.g., diltiazem, verapamil) are recommended because of
their effect on the myocardium and heart rate. These calcium channel blockers may also be indicated in patients
who would be candidates for β-blockers but are intolerant of these agents. Digoxin is also a less well-established
option for patients who are frequently hospitalized (HFSA
2010a; Hunt 2009; Dickstein 2008).
Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus
no propranolol on total mortality plus nonfatal myocardial
infarction in older patients with prior myocardial infarction,
congestive heart failure, and left ventricular ejection fraction ≥ 40% treated with diuretics plus angiotensin-converting
enzyme inhibitors. Am J Cardiol 1997;80:207-9.
PubMed Link
Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac
comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved
versus reduced ejection fraction. J Am Coll Cardiol
2012;59:998-1005.
PubMed Link
Barnes MM, Dorsch MP, Hummel SL, et al. Treatment
of heart failure with preserved ejection fraction.
Pharmacotherapy 2011;31:312-31.
PubMed Link
Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med
2008;358:1887-98.
PubMed Link
Bella JN, Palmieri V, Roman MJ, et al. Mitral ratio of peak
early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study.
Circulation 2002;105:1928-33.
PubMed Link
Conclusion (A)
Because HFpEF is still not well understood, more research
is needed to better understand the pathophysiology and
progression of this clinical syndrome. Patient diagnosis is primarily based on clinical symptoms and echocardiography,
although biomarkers may have an emerging future role. Agerelated diseases are commonly observed with HFpEF, and
treatment should be targeted to reduce comorbidity burden.
Although experimental studies appear to support a pathophysiologic and mechanistic rationale for therapy, strong
clinical evidence is lacking. Therefore, current guidelines are
largely empiric, focusing on patient signs and symptoms of
HF and standard therapies used for reduced EF. Several large
randomized clinical studies are investigating both standard
and novel agents for HFpEF.
Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol
on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish
Doppler-Echocardiographic Study (SWEDIC). Eur J Heart
Fail 2004;6:453-61.
PubMed Link
Borlaug BA, Paulus WJ. Heart failure with preserved ejection
fraction: pathophysiology, diagnosis, and treatment. Eur Heart
J 2011;32:670-9.
PubMed Link
Braunwald E. Biomarkers in heart failure. N Engl J Med
2008;358:2148-59.
PubMed Link
Budaj A, Kokowicz P, Smielak-Korombel W, et al. Lack of
effect of amiodarone on survival after extensive infarction.
Polish Amiodarone Trial. Coron Artery Dis 1996;7:315-9.
PubMed Link
References
Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in
mortality and hospitalization in heart failure: a comprehensive
post hoc analysis of the DIG trial. Eur Heart J 2006;27:178-86.
PubMed Link
Burkart F, Pfisterer M, Kiowski W, et al. Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction
with asymptomatic complex ventricular arrhythmias: Basel
antiarrhythmic study of infarct survival (BASIS). J Am Coll
Cardiol 1990;16:1711-8.
PubMed Link
Alagiakrishnan K, Banach M, Jones LG, et al. Update on diastolic heart failure or heart failure with preserved ejection
fraction in older adults. Ann Med 2012;1-14. [Epub ahead of
print]
PubMed Link
Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic
heart failure in the community. JAMA 2006;296:2209-16.
PubMed Link
Anand IS, Rector TS, Cleland, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and
its interactions with irbesartan treatment effects in patients
with heart failure and preserved ejection fraction: findings
from the I-PRESERVE Trial. Circ Heart Fail 2011;4:569-77.
PubMed Link
PSAP 2013 • Cardiology/Endocrinology
Connolly SJ, Camm J, Halperin JL, et al. Dronedarone
in high-risk permanent atrial fibrillation. N Engl J Med
2011;365:2268-76.
PubMed Link
13
Heart Failure with Preserved Ejection Fraction
Daniel KR, Wells G, Stewart K, et al. Effect of aldosterone
antagonism on exercise tolerance, Doppler diastolic function,
and quality of life in older women with diastolic heart failure.
Congest Heart Fail 2009;15:68-74.
PubMed Link
for Heart and Lung Transplantation: endorsed by the Heart
Rhythm Society. Circulation 2005;112:e154-235.
PubMed Link
Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update
incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the
American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines: developed
in collaboration with the International Society for Heart and
Lung Transplantation. Circulation 2009;119:e391-479.
PubMed Link
Davis BR, Kostis JB, Simpson LM, et al. Heart failure with
preserved and reduced left ventricular ejection fraction in the
antihypertensive and lipid-lowering treatment to prevent heart
attack trial. Circulation 2008;118:2259-67.
PubMed Link
De Boer RA, Lok DJ, Jaarsma T, et al. Predictive value of
plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011;43:60-8.
PubMed Link
Jacobshagen C, Belardinelli L, Hasenfuss G, et al. Ranolazine
for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF Study.
Clin Cardiol 2011;34:426-32.
PubMed Link
Desai AS, Lewis EF, Li R, et al. Rationale and design of the
treatment of preserved cardiac function heart failure with an
aldosterone antagonist trial: a randomized, controlled study of
spironolactone in patients with symptomatic heart failure and
preserved ejection fraction. Am Heart J 2011;162:966-72.e10.
PubMed Link
Jessup M, Abraham WT, Casey DE, et al. 2009 focused
update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American
College of Cardiology Foundation/American Heart
Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung
Transplantation. Circulation 2009;119:1977-2016.
PubMed Link
Fang Y, Debunne M, Vercauteren M, et al. Heart rate reduction
induced by the current inhibitor ivabradine improves diastolic
function and attenuates cardiac tissue hypoxia. J Cardiovasc
Pharmacol 2012;59:260-7.
PubMed Link
Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al.
Inflammatory markers and incident heart failure risk in older
adults. J Am Coll Cardiol 2010;55:2129-37.
PubMed Link
Fukuta H, Sane DC, Brucks S, et al. Statin therapy may be
associated with lower mortality in patients with diastolic heart
failure: a preliminary report. Circulation 2005;112:357-63.
PubMed Link
Kitzman DW, Little WC, Brubaker PH, et al.
Pathophysiological characterization of isolated diastolic
heart failure in comparison to systolic heart failure. JAMA
2002;288:2144-50.
PubMed Link
Gaasch WH. Diagnosis and treatment of heart failure based
on left ventricular systolic or diastolic dysfunction. JAMA
1994;271:1276-80.
PubMed Link
Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with
isolated systolic hypertension. SHEP Cooperative Research
Group. JAMA 1997;278:212-6.
PubMed Link
Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of
acute pulmonary edema associated with hypertension. N Engl
J Med 2001;344:17-22.
PubMed Link
Hay I, Rich J, Ferber P, et al. Role of impaired myocardial
relaxation in the production of elevated left ventricular filling
pressure. Am J Cardiol 2004;288:H1203-H1208.
PubMed Link
Krum H, Elsik M, Schneider HG, et al. Relationship of peripheral collagen markers to death and hospitalisation in patients
with heart failure and preserved ejection fraction: results
of the I-PRESERVE Collagen sub-study. Circ Heart Fail
2011;4:561-8.
PubMed Link
Heart Failure Society of America. Executive summary: HFSA
2010 comprehensive heart failure practice guidelines. J Card
Fail 2010a;16:475-539.
PubMed Link
Little WC, Zile MR, Kitzman DW, et al. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker,
in the treatment of elderly patients with diastolic heart failure.
J Card Fail 2005;11:191-5.
PubMed Link
Hung MJ, Cherng WJ, Kuo LT, et al. Effect of verapamil
in elderly patients with left ventricular diastolic dysfunction as a cause of congestive heart failure. Int J Clin Pract
2002;56:57-62.
PubMed Link
Maisel AS, McCord J, Nowak RM, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with
reduced or preserved ejection fraction. J Am Coll Cardiol
2003;41:2010-7.
PubMed Link
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005
guideline update for the diagnosis and management of chronic
heartfailure in the adult: a report of the American College of
Cardiology/American Heart Association task force on practice guidelines: developed in collaboration with the American
College of Chest Physicians and the International Society
Heart Failure with Preserved Ejection Fraction
Mak GJ, Ledwidge MT, Watson CJ, et al. Natural history of
markers of collagen turnover in patients with early diastolic
14
PSAP 2013 • Cardiology/Endocrinology
dysfunction and impact of eplerenone. J Am Coll Cardiol
2009;54:1674-82.
PubMed Link
PubMed Link
Roongsritong C, Sutthiwan P, Bradley J, et al. Spironolactone
improves diastolic function in the elderly. Clin Cardiol
2005;28:484-7.
PubMed Link
Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in
patients with heart failure and preserved ejection fraction. N
Engl J Med 2008;359:2456-67.
PubMed Link
Schunkert H, Jackson B, Tang SS, et al. Distribution and functional significance of cardiac angiotensin converting enzyme
in hypertrophied rat hearts. Circulation 1993;87:1328-39.
PubMed Link
McKee PA, Castelli WP, McNamara PM, et al. The natural history of congestive heart failure: the Framingham study. N Engl
J Med 1971;285:1441-6.
PubMed Link
Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal left
ventricular diastolic filling and normal left ventricular systolic
performance. Am J Cardiol 1990;66:981-6.
PubMed Link
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic
heart failure 2012: the Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure 2012 of the
European Society of Cardiology. Developed in collaboration
with the Heart Failure Association (HFA) of the ESC. Eur J
Heart Fail 2012;14:803-69.
PubMed Link
Shah R, Wang Y, Foody JM. Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in
patients ≥ 65 years of age with heart failure and preserved left
ventricular systolic function. Am J Cardiol 2008;101:217-22.
PubMed Link
McMurray JJ, Carson PE, Komajda M, et al. Heart failure with
preserved ejection fraction: clinical characteristics of 4133
patients enrolled in the I-PRESERVE trial. Eur J Heart Fail
2008;10:149-56.
PubMed Link
Smith GL, Masoudi FA, Vaccarino V, et al. Outcomes in heart
failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol
2003;41:1510-8.
PubMed Link
Meyer P, White M, Mujib M, et al. Digoxin and reduction of
heart failure hospitalization in chronic systolic and diastolic
heart failure. Am J Cardiol 2008;102:1681-6.
PubMed Link
Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor
neprilysin inhibitor LCZ696 in heart failure with preserved
ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet 2012 Aug 24. [Epub ahead of print]
PubMed Link
Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in
hypertensive patients with diastolic heart failure. Circulation
2004;110:558-65.
PubMed Link
Takimoto E, Champion HC, Li M, et al. Chronic inhibition of
cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214-22.
PubMed Link
Owan T, Hodge DO, Herges RM, et al. Trends in prevalence
and outcome of heart failure with preserved ejection fraction.
N Engl J Med 2006;355:251-9.
PubMed Link
Tehrani F, Morrissey R, Phan A, et al. Statin therapy in patients with diastolic heart failure. Clin Cardiol
2010;33:E1-E5.
PubMed Link
Packer M. Can brain natriuretic peptide be used to guide the
management of patients with heart failure and a preserved
ejection fraction? The wrong way to identify new treatments
for a nonexistent disease. Circ Heart Fail 2011;4:538-40.
PubMed Link
Thohan V, Koerner MM, Pratt CM, et al. Improvements in
diastolic function among patients with advanced systolic
heart failure utilizing alagebrium (an oral advanced glycation
end-product cross-link breaker). Circulation 2005;112(suppl
2):2647.
Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the
diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography
Associations of the European Society of Cardiology. Eur Heart
J 2007;28:2539-50.
PubMed Link
Tribouilloy C, Rusinaru D, Mahjoub H, et al. Prognostic
impact of diabetes mellitus in patients with heart failure and
preserved ejection fraction: a prospective five-year study.
Heart 2008;94:1450-5.
PubMed Link
Phan TT, Shivu GN, Abozguia K, et al. Impaired heart rate
recovery and chronotropic incompetence in patients with
heart failure with preserved ejection fraction. Circ Heart Fail
2010;3:29-34.
PubMed Link
Redfield MM, Jacobsen SJ, Burnett JC, et al. Burden of systolic and diastolic ventricular dysfunction in the community.
JAMA 2003;289:194-202.
PubMed Link
van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Betablockade with nebivolol in elderly heart failure patients with
impaired and preserved left ventricular ejection fraction. J Am
Coll Cardiol 2009;53:2150-8.
Roger VL, Go AS, Lloyd-Jones, et al. Heart disease and stroke
statistics--2011 update: a report from the American Heart
Association. Circulation 2011;123:e18-e209.
PSAP 2013 • Cardiology/Endocrinology
15
Heart Failure with Preserved Ejection Fraction
PubMed Link
Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart
failure in subjects with normal versus reduced left ventricular
ejection fraction: prevalence and mortality in a populationbased cohort. J Am Coll Cardiol 1999;33:1948-55.
PubMed Link
Weber KT. Aldosterone in congestive heart failure. N Engl J
Med 2001;345:1689-97.
PubMed Link
Westermann D, Richter RA, Jager S, et al. Enhancement of the
endothelial NO synthase attenuates experimental diastolic
heart failure. Basic Res Cardiol 2009;104:499-509.
PubMed Link
Williams ES, Shah SJ, Ali S, et al. C-reactive protein, diastolic
dysfunction, and risk of heart failure in patients with coronary
disease: Heart and Soul Study. Eur J Heart Fail 2008;10:63-9.
PubMed Link
Yamamoto K, Masayama T, Sakata Y, et al. Roles of reninangiotensin and endothelin systems in development of
diastolic heart failure in hypertensive hearts. Cardiovasc Res
2000;47:274-83.
PubMed Link
Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic
heart failure study: a randomized controlled 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;94:573-80.
PubMed Link
Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure –
abnormalities in active relaxation and passive stiffness of the
left ventricle. N Engl J Med 2004;350:1953-9.
PubMed Link
Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure. Part I: diagnosis, prognosis,
and measurements of diastolic function. Circulation
2002a;105:1387-93.
PubMed Link
Zile MR, Brutsaert DL. New concepts in diastolic dysfunction
and diastolic heart failure. Part II:
causal mechanisms and treatment. Circulation
2002b;105:1503-8.
PubMed Link
Zile MR, Gaasch WH, Anand IS, et al. Mode of death in
patients with heart failure and a preserved ejection fraction.
Circulation 2010;121:1393-405.
PubMed Link
Heart Failure with Preserved Ejection Fraction
16
PSAP 2013 • Cardiology/Endocrinology
Self-Assessment Questions
1. A 49-year-old man has heart failure with preserved
ejection fraction (HFpEF), diabetes mellitus,
and hypertension. His blood pressure, which has
improved during the past several months, is currently
140/75 mm Hg with a heart rate of 70 beats/minute.
His home drugs include hydrochlorothiazide 25 mg/
day and metoprolol 50 mg twice daily. Which one of
the following would best prevent the progression of
HFpEF in this patient?
C.Hypertension.
D. Mitral regurgitation.
4. Which one of the following best describes the number
of risk factors for HFpEF present in R.P.?
A.One.
B.Two.
C.Three.
D.Four.
A.Digoxin.
B.Candesartan.
C.Amiodarone.
D.Diltiazem.
5. Which one of the following best differentiates HFpEF
from heart failure with reduced ejection fraction
(HFrEF) in R.P.?
A. S4 gallop.
B.JVP.
C. Progressive dyspnea.
D.LVEF.
2. Which one of the following best describes moderate
diastolic impairment on echocardiography?
A.
B.
C.
D.
Left atrial pressure.
Pulmonary artery pressure.
Left ventricular size.
E/A ratio.
6. Which one of the following is the best interpretation
of R.P.’s NT-proBNP results?
A. B-type natriuretic protein (BNP) would provide
more utility than NT-proBNP.
B. Both BNP and NT-proBNP concentrations
should be assessed.
C. Galectin-3 would better identify diastolic
dysfunction than NT-proBNP.
D. The utility of NT-proBNP may be confounded
by the patient’s comorbidities.
Questions 3–9 pertain to the following case.
R.P. is an 80-year-old woman (height 5′5′′, weight 127
lb) being seen in the heart failure (HF) clinic. She has
a 2-week history of progressive dyspnea, 1+ peripheral
edema, and mild bronchiectasis. She also has a longstanding history of hypertension and recently received
diagnoses of atrial fibrillation and kidney insufficiency.
On physical examination, her blood pressure is 145/80
mm Hg, and her heart rate is irregular at 65 beats/minute; her jugular venous pressure (JVP) is 12 cm with a
marked v wave. Auscultation detects bibasilar rales, a 2/6
systolic ejection murmur at the left sternal border, and an
S4 gallop. There is also bilateral 2+ pitting edema in the
lower extremities. Her echocardiography report indicates
a left ventricular ejection fraction (LVEF) of 55%, biatrial
enlargement, left atrial mean pressure of 19 mm Hg (normal 4–12 mm Hg), pulmonary artery pressure of 55 mm
Hg (normal 15–30 mm Hg), right atrial pressure of 10
mm Hg (normal 2–6 mm Hg), and severe tricuspid regurgitation and mild mitral regurgitation. Her N-terminal
pro–B-type natriuretic peptide (NT-proBNP) concentration is 240 pg/mL, and CrCL is 25 mL/minute. R.P.’s
current drugs, all taken orally, include amlodipine 10 mg/
day, warfarin 4 mg/day, metoprolol 25 mg twice daily, and
irbesartan 150 mg/day.
7. Which one of the following would be the most appropriate blood pressure goal for R.P.?
A.
B.
C.
D.
8. Which one of the following would be the best
add-on antihypertensive therapy for R.P.?
A. Furosemide 40 mg/day.
B. Verapamil SR 180 mg/day.
C. Hydrochlorothiazide 25 mg/day.
D. Spironolactone 12.5 mg/day.
9. Which one of the following lifestyle modifications
would be most appropriate for R.P.?
A.
B.
C.
D.
3. Which one of the following best describes the primary cause of R.P.’s clinical presentation?
A. Atrial fibrillation.
B. Left-sided filling pressures.
PSAP 2013 • Cardiology/Endocrinology
Less than 140/90 mm Hg.
Less than 135/85 mm Hg.
Less than 130/80 mm Hg.
Less than 120/75 mm Hg.
17
Restrict sodium intake to less than 2–3 g/day.
Reduce body mass index to less than 18.
Restrict fluid intake to less than 1.5 L/day.
Initiate a high-carbohydrate diet.
Heart Failure with Preserved Ejection Fraction
10. Which one of the following best describes the risk of
death in patients with HFpEF compared with HFrEF?
D.Dronedarone.
14. E.W.’s blood pressure is currently 118/70 mm Hg. The
cardiologist initiates a statin but requests your advice
about the potential benefits it could provide. Which
one of the following is the best reason to initiate a
statin in E.W.?
A. Diabetes mellitus and cerebrovascular accident
increase risk of death in HFpEF versus HFrEF.
B. Diabetes mellitus and cerebrovascular accident
increase risk of death in HFrEF versus HFpEF.
C. Diabetes mellitus, but not cerebrovascular
accident, increases risk of death in HFpEF versus
HFrEF.
D. Cerebrovascular accident, but not diabetes
mellitus, increases risk of death in HFpEF versus
HFrEF.
A.
B.
C.
D.
15. A 55-year-old woman with HFpEF comes to the outpatient medicine clinic. Her blood pressure is 135/85
mm Hg, and her heart rate is 130 beats/minute. She
has no other comorbidities or abnormalities. Which
one of the following would be best to initiate in this
patient?
Questions 11–14 pertain to the following case.
E.W. is a 71-year-old man (height 5′7′′, weight 300 lb) with
a 1-year history of hypertension. After an aortic valve
replacement for aortic stenosis, he was referred to your HF
clinic with increasing dizziness during the past few days.
His medical history is significant for chronic obstructive
pulmonary disease (COPD). Results of his physical examination are blood pressure 89/55 mm Hg (baseline 125/87
mm Hg), heart rate 120 beats/minute, and Sao2 95% on
room air. E.W. has no JVP, rales, or edema, but distant
heart sounds with 1/6 systolic ejection murmur are noted.
He has no other significant physical findings. Chest radiography is clear with no infiltrates. His laboratory findings
include SCr 3.0 mg/dL (previously 1.0) and BUN 63 mg/
dL. E.W.’s current oral drugs include warfarin 5 mg/day,
amlodipine 10 mg/day, furosemide 60 mg/day, and inhalers. His echocardiography report shows an EF of 55%.
Serum lipids are TC 220 mg/dL, LDL cholesterol 135
mg/dL, HDL cholesterol 55 mg/dL, and TG 150 mg/dL.
A.Enalapril.
B.Metoprolol.
C.Diltiazem.
D.Hydrochlorothiazide.
16. You are asked by the multidisciplinary team to provide information about the role of advanced glycation
end-product crosslink breakers in HFpEf. Which one
of the following statements most accurately describes
these novel agents?
A. They act on excessive crosslinks in the
myocardium but not on vasculature.
B. They reduce left ventricular mass, diastolic
function, and remodeling.
C. They reduce intracellular calcium, leading to
improved diastolic relaxation.
D. They reduce pressure-induced ventricular
hypertrophy and fibrosis.
11. Given E.W.’s presentation, which one of the following
etiologies is most likely responsible for his HFpEF?
A.Hypertension.
B. Aortic stenosis.
C.COPD.
D.Obesity.
17. A 82-year-old woman recently received a diagnosis
of HFpEF and new-onset cough. She has a history of
obesity, diabetes mellitus, and hypertension. From
her history, which one of the following best describes
this patient’s number of modifiable risk factors?
12. Which one of the following is most appropriate for
E.W. at this time?
A.
B.
C.
D.
Increase his dose of inhalers.
Assess his INR.
Reduce amlodipine to 5 mg orally daily.
Reduce furosemide dose to 20 mg/day.
A.One.
B.Two.
C.Three.
D.Four.
13. Although E.W. is no longer experiencing dizziness, he
has new-onset atrial fibrillation with rapid ventricular
response. Which one of the following would be best
to recommend for cardioversion in this patient?
18. Which one of the following best describes the difference between the prognoses of HFrEF and HFpEF?
A. The short-term mortality rate is lower with
HFrEF than with HFpEF.
B. The long-term mortality rate is lower with
HFrEF than with HFpEF.
A.Dofetilide
B.Diltiazem.
C.Amiodarone.
Heart Failure with Preserved Ejection Fraction
Improve HDL cholesterol.
Improve LDL cholesterol.
Increase fibrosis.
Reduce afterload.
18
PSAP 2013 • Cardiology/Endocrinology
C. The functional status of patients with HFrEF is
similar to that of patients with HFpEF.
D. Functional status declines over time with both
HFpEF and HFrEF.
19. Which one of the following best describes the current evidence supporting the potential role of
spironolactone in patients with HFpEF?
A. Reduces fibrosis and inflammation in
experimental studies.
B. Improves diastolic function through
antihypertensive effects.
C. Improves left ventricular long-axis strain rate
after 6 months of therapy.
D. Reduces sudden cardiac death in symptomatic
patients.
20. Which one of the following is most prevalent in both
types of HF?
A.Cardiomegaly.
B.S3.
C.JVD.
D. Paroxysmal nocturnal dyspnea.
PSAP 2013 • Cardiology/Endocrinology
19
Heart Failure with Preserved Ejection Fraction