CHAPTER 27: Heart Failure with a Preserved Ejection Fraction

Ma. Arnee V. Anico-Tondo,M.D., FPCP (CGH)

 Patients with heart failure can be divided into those with:

(1) heart failure with a reduced ejection fraction (HFrEF) and
(2) heart failure with a preserved ejection fraction (HFpEF)
 Patients with HFpEF have a:
 Devastating 5-year mortality rate (approaching 60%)
 Costly morbidity (6-month hospitalization rate of 50%)
 Debilitating symptoms (maximum myocardial oxygen consumption [MVO2] averaging 14 mL/g/min)
 Patients with preserved EF are older and more likely to be female; however, HFpEF occurs in both men and women
throughout the 5th to the 9th decades of life
SYSTOLIC  Most common antecedent disease leading to HFpEF
HYPERTENSION  Present in more than 85% of patients
 Ischemic heart disease is much less common than in HFrEF
 Patients with HFpEF have normal LV end-diastolic volume and normal (or near-normal) EF and stroke volume and
commonly exhibit concentric remodeling of either LV chamber and/or cardiomyocytes
 Standard heart failure therapy shown to be effective in HFrEF has not been found to reduce morbidity or mortality
associated with HFpEF, leaving a substantial area of unmet need
EPIDEMIOLOGY
 Substantial proportion (more than 50% in many studies) of patients who are diagnosed or hospitalized with heart failure have
HFpEF
 Prevalence of HFpEF increases dramatically with age
 Much more common in women than in men at any age
 Distribution of EF across unselected populations of patients with heart failure is bimodal, with peaks centered on 35% and
55% ( Data from OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart
Failure) registry and examined EF in 48,612 subjects)

Chapter 27: Heart Failure with a Preserved Ejection Fractions

NATURAL HISTORY
MORTALITY
 5-year survival rate for all patients with heart failure, regardless of EF, is less than 50%
FIGURE 27-1 Prevalence and heart failure–related hospital admissions in patients with HFpEF
A, The percentage of patients with the HFpEF form of heart failure increased from 1987 to 2001, demonstrating that HFpEF
prevalence continues to rise
B, Over this same 15-year time frame, the number of heart failure– related hospitalizations in patients with HFrEF
remained stable or trended slightly downward, whereas in patients with HFpEF, the number increased significantly
 Data from epidemiologic studies of HFpEF find that the annual mortality is approximately 10%, but RCTs in patients with
HFpEF suggest that the annual mortality is about 5%
 In the RCTs, patients with HFpEF, who have antecedent and comorbid factors such as hypertension, coronary artery disease
and diabetes mellitus, were found to have more than twice the mortality rate of patients with hypertension, coronary artery
disease, or diabetes who do not have HFpEF
MODE OF DEATH
 Most (>70%) of the deaths in patients with HFpEF are cardiovascular in nature, with 20% due to heart failure and 35% due to
sudden death
 Incidence of noncardiovascular deaths is significantly higher for HFpEF (30%) than for HFrEF (15%), reflecting the higher age and
increased comorbidity in patients with HFpEF

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MORBIDITY
 Heart failure–related hospital readmission rates approximate 50% at 6 months for both HFrEF and HFpEF
 Rates of progressive functional decline after hospital admission for heart failure also are similar in patients with HFpEF and in
those with HFrEF
 Abnormalities in exercise tolerance, MVO2, and quality-of-life assessment are similar for HFrEF and HFpEF
CONVERSION FROM HEART FAILURE WITH PRESERVED EJECTION FRACTION TO HEART FAILURE WITH
REDUCED EJECTION FRACTION
 Uncommon and generally is associated with an incident injury (such as myocardial ischemia)
 One study, 1233 patients with heart failure had serial echocardiograms to determine the time course of changes in the LV EF over a 5-year
observation period
 On average, the LV EF decreased by approximately 0.06 over 5 years in the HFpEF group, whereas it increased by nearly 0.07 in the HFrEF
group.
 Rates should be interpreted in light of the following limitations: HFpEF and HFrEF were divided on the basis of an EF of 50%, no uniform
deterioration in EF occurred in patients with HFpEF
 Study of 343 subjects with concentric LV remodeling (but no heart failure) found that over 7 years, only 7% developed eccentric
remodeling with LV dilation and a fall in EF
 Although treatment of HFrEF may result in normalization of EF, a decline in EF in HFpEF appears usually to be due to an
intercurrent event, most frequently ischemic injury
PATHOPHYSIOLOGY
 Pathophysiologic mechanisms that cause the development of HFpEF are reflected in changes in LV relaxation and filling, LV
structural remodeling and altered geometry, and changes in LV and vascular compliance

Chapter 27: Heart Failure with a Preserved Ejection Fractions

NORMAL DIASTOLIC PROPERTIES

 Normal diastolic function allows the ventricle to fill adequately during rest and exercise, without an abnormal increase in left
atrial (LA) pressure
 Phases of diastole:
 Isovolumic pressure decline and filling

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  Filling phase is divided into early rapid filling, diastasis, and atrial systole
 Contributes 70% to 80% of LV filling in normal individuals
 Contribution diminishes with age and various disease states
 Early diastolic filling is driven by the LA-to-LV pressure gradient, which is dependent on a
complex interplay of factors:
EARLY RAPID FILLING
- Myocardial relaxation
- LV elastic recoil
- LV diastolic stiffness
- LA pressures
- Ventricular interaction
- Pericardial constraint
- Pulmonary vein properties
- Mitral orifice area
 Occurs in mid-diastole
DIASTASIS  When the LA and LV pressures usually are almost equal
 It contributes less than 5% of the LV filling, and its duration shortens with tachycardia
 In normal subjects, contributes 15% to 25% of LV diastolic filling without raising the mean LA
pressure
ATRIAL SYSTOLE  Contribution depends on the PR interval, atrial inotropic state, atrial preload, atrial afterload,
autonomic tone, and heart rate
LEFT VENTRICULAR RELAXATION
 Active, energy-dependent process
 Begins with the decay of force-generating capacity, follows the completion of the ejection phase of systole, and continues
through isovolumic pressure decline and the rapid filling phase
 Filling is dependent both on active relaxation and on the recoil/suction that results from the release of potential energy
stored during systole by contraction. Thus blood is effectively “pulled” into the left ventricle
 In normal hearts, over a range of normal heart rates, relaxation and recoil are adequate to allow LA pressures to remain
normal
 In addition, catecholamine induced enhancement of relaxation and recoil during exercise lowers LV pressures in early
diastole, thereby increasing the LA-to-LV pressure gradient without increasing LA pressures as well as enhancing filling
during exercise
 In patients with HFpEF, relaxation and recoil are abnormal at rest and are not enhanced during increased HR or exercise
 As a result, filling can be maintained only by increased LA pressure; blood must be “pushed” into the left ventricle
ISOVOLUMIC PRESSURE DECLINE
 Time course of isovolumetric pressure decline has been quantitatively described by the peak rate of pressure fall (dP/dt min)

Chapter 27: Heart Failure with a Preserved Ejection Fractions

and the time constant τ (tau) of the exponential fall in LV isovolumetric pressure
 dP/dtmin measures the rate of pressure decline at a single point in time, is strongly influenced by the LV pressure at the
time of aortic valve closure, and therefore, like all indices of diastolic function, is afterload-dependent
 Patients with HFpEF have a larger dP/dtmin, signifying that relaxation rate is decreased
 Time constant τ describes the rate of LV pressure decline throughout isovolumic relaxation
 Pressure (P) and time (t) data during the period from end-systole (aortic valve closure) to the onset of LV filling (mitral
valve opening) are fit to an exponential equation such as the following:
LV pressure = P0e−t/τ
Where:
P0 is LV pressure at end ejection
τ is the exponential time constant
 The larger the value of τ, the longer it takes for the LV pressure to fall and the more impaired is relaxation
 A normal value for τ is less than 40 milliseconds in most age groups, suggesting that relaxation is nearly complete by 3.5 ×
τ (less than 140 milliseconds)
 Can be estimated by echo techniques as the time between aortic valve closure and mitral valve
Isovolumic relaxation opening
time (IVRT  Useful in the noninvasive assessment of diastolic properties. However, depends not only on the
rate of LV relaxation but also on the aortic pressure at the time of aortic valve closure and the LA

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 pressure at mitral valve opening
 Can be increased by an elevation of aortic pressure or decreased by an increase in LA pressure
 Time course of LV pressure decline during isovolumetric relaxation can also be characterized using noninvasive Doppler
measurement of the velocity of a regurgitant jet across the mitral valve
 Modified Bernoulli equation is used to approximate LV pressure during isovolumetric relaxation, allowing calculation of
the maximum rate of LV pressure decline and the exponential time constant
RECOIL AND LEFT VENTRICULAR FILLING
 During systole, potential energy is stored in the elastic elements of the cardiomyocytes and extracellular matrix (ECM)
 Elastic elements are compressed and twisted during systolic contraction
 During relaxation, this potential energy is released as the elastic elements recoil and return to their original length and
orientation
 Recoil causes LV pressure to fall rapidly during isovolumetric relaxation
 For the first 30 to 40 milliseconds after mitral valve opening, the relaxation of LV wall tension normally is rapid enough to
cause LV pressure to continue to decline despite an increase in LV volume
 This fall in LV pressure produces an early diastolic pressure gradient from the LA that extends to the LV apex
 This accelerates blood out of the LA and produces rapid early diastolic flow that quickly propagates to the apex
 Because the diastolic intraventricular pressure gradient pulls blood to the apex, it can be considered a measure of LV
suction
 It is reduced in patients with ischemia, hypertrophic cardiomyopathy, and heart failure including HFpEF
 Because the LV apex remains fixed during the cardiac cycle, the mitral annular velocity provides a measure of long-axis
lengthening rate
 Under normal conditions, peak early diastolic mitral annular velocity (e’) occurs coincidentally with or before the mitral E
 This is a manifestation of the symmetric expansion of the left ventricle in early diastole as blood moves rapidly to the LV
apex in response to a progressive pressure gradient from the left atrium to the LV apex
 Rapid recoil of the mitral annulus and valve into the left atrium early in diastole relocates blood from the left atrium into
the left ventricle
 Under normal circumstances, both E and e’ respond to changes in the LA-to-LV pressure gradient.
 For example, both E and e′ normally increase in response to increased volume load and exercise
DETERMINANTS OF LEFT VENTRICULAR RELAXATION 
 Hemodynamic load (early diastolic load and afterload)
 Myofiber inactivation
 Uniformity of the distribution of load and inactivation in space and time (dyssynchrony, dyssynergy, Treppe)
HEMODYNAMIC LOAD

Chapter 27: Heart Failure with a Preserved Ejection Fractions

 Both isovolumic pressure decline and early filling are affected by afterload (LV systolic stress)
 An increase in LV systolic stress results in a delay in and slowed rate of pressure decline and early filling
 Increases in LV pressure late in systole hasten the onset of LV relaxation, but relaxation occurs at a slower rate (increased τ)
 Increases in LV pressure late in systole occur with aging because of age-related vascular stiffening, which alters the timing of
reflected pressure wave in the vascular tree so that the reflected wave arrives in late systole rather than diastole
 An acute increase in blood pressure either at rest or during exercise will impair ejection, slow pressure decline, prolong time
to complete relaxation, and reduce recoil
 These changes in relaxation decrease the LA-to-LV gradient, decrease early filling, and result in increased LV diastolic and LA
pressure
HETEROGENEITY
Will enhance LV relaxation...
Synchrony (timing of relaxation of the different myocardial segments)
synergy (extent to which myocardial segments relax)
Dyssynchrony or dyssynergy (e.g., caused by infarction, ischemia, asymmetry of hypertrophy, or conduction abnormalities)
will impair global LV relaxation
 Dyssynchrony, measured using a variety of echocardiographic measurements, may be present in patients with HFpEF,
particularly those with left bundle branch block (LBBB) or right ventricular (RV) pacing
CELLULAR MECHANISM
 Myofiber inactivation refers to the many cellular processes that ultimately influence the process by which the left ventricle,

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 its constitutive cardiomyocytes and individual sarcomeres return to a normal end-diastolic length with minimum cross-
bridge cycling and low force generation
 To accomplish this state of complete relaxation requires:
(1) Calcium resequestration into the sarcoplasmic reticulum, followed by calcium extrusion into the extracellular space;
(2) Availability of sufficient ATP
(3) Normal myofilament function
(4) Normal elastic properties of the cardiomyocyte and the ECM
PREVALENCE AND PROGNOSIS FOR ABNORMAL RELAXATION
 Impaired relaxation is present in HFpEF and contributes to the development of elevated LA pressure at rest
 Rate of relaxation is further impaired during exercise and hemodynamic stress
 Factor that shortens the diastolic filling period (prolonged contraction or long PR interval) will enhance the effect of
impaired relaxation on LV diastolic pressures during filling and thus affect the mean LA pressure needed to fill the left
ventricle
LEFT VENTRICULAR DIASTOLIC STIFFNESS, COMPLIANCE, AND DISTENSIBILITY 
METHODS OF MEASUREMENT
 Passive characteristics of the left ventricle during diastole can be described by the passive diastolic pressure-volume
relationship (DPVR)
 Resultant DPVR is nonlinear and can be approximated by an exponential function
LV stiffness  Defined as the ratio of LV diastolic pressure and LV diastolic volume (LV dP/dV) at any given LV
diastolic volume
LV compliance  Reciprocal of stiffness (LV dV/dP)
 Because the DPVR can be approximated as an exponential, stiffness will increase as the left ventricle fills to higher LV
diastolic volumes; thus as the left ventricle fills, it becomes stiffer
LV  Defined as the end-diastolic pressure required to distend the left ventricle to an end-diastolic
diastolic distensibility volume
 Patients with HFpEF have reduced distensibility, indicated by a normal or reduced end-diastolic volume and an elevated
end diastolic pressure
 β does not indicate stiffness but instead describes how rapidly stiffness increased with increases in volume (β = [dP/dV]/V)
 Patients with HFpEF have abnormal DPVRs with elevated β and abnormal distensibility

Chapter 27: Heart Failure with a Preserved Ejection Fractions

FIGURE 27-4 Difference in diastolic chamber distensibility in patients with HFpEF (in red) versus HFrEF (in black) versus
age- and gender-matched referent control subjects (in green)
 Diastolic pressure-volume relationship in patients with HFpEF is shifted upward and to the left, such that for any given LV
volume, pressure is higher in HFpEF, indicating decreased distensibility (increased stiffness)
 By contrast, in patients with HFrEF, the diastolic pressure-volume relationship is shifted to the right, indicating increased
distensibility

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 Patients with heart failure and an increased LV diastolic pressure can be divided into four groups defined by patterns of
DPVR (Diastolic Pressure Volume Relationship)

FIGURE 27-5 Mechanisms that result in increased LV diastolic pressure

 DPVR in patients with HFpEF may be characterized by graphed curves A to C
 In the most prevalent pattern in HFpEF, represented by curve B, the DPVR is shifted upward and to the left, indicating
reduced distensibility, where LV pressure is increased at any LV volume
 In patients with HFpEF, when relaxation is markedly prolonged and diastole is abbreviated, as shown in curve A, LV diastolic
pressure falls throughout diastole but remains increased
 In curve C, pericardial constraint causes a parallel upward shift in the DPVR
 DPVR in patients with HFrEF typically is characterized by curve D, in which eccentric remodelling results in a shift of the
DPVR to the right, representing an increase in distensibility
 It should be recognized that although the ventricle is more distensible, the end diastolic volume in these patients typically is
very large and the end-diastolic stiffness in the operating region is high
DETERMINANTS OF LEFT VENTRICULAR PRESSURE-VERSUS-VOLUME RELATIONSHIP
 Two of the determinants associated with an upward and leftward shift of the DPRV in patients with HFpEF are the:
 Presence of LV and cardiomyocyte concentric remodeling
 Hypertrophy and changes in the material properties of myocardial muscle itself (i.e., myocardial stiffness)
 Myocardial diastolic stiffness can be determined by assessing the myocardial diastolic LV stress versus strain relationship

Chapter 27: Heart Failure with a Preserved Ejection Fractions

 Stress-strain relationship represents the resistance of the myocardium to stretch (increase in length) when subjected to stress
(distending force)

FIGURE 27-6 Changes in cardiomyocyte structure (A-C) and extracellular matrix fibrillar collagen (D-F) in HFpEF (outlined in red) versus HFrEF
(outlined in black) versus findings in referent control group (outlined in green). Arrows indicate fibrillar collagen
 HFpEF is associated with concentric cardiomyocyte remodeling with increased diameter but no change in length and increased fibrillar
collagen content, thickness, and number
 HFrEF is associated with eccentric cardiomyocyte remodeling with increased length but no change in width and fibrillar collagen

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 degradation and abnormal structure and turnover
CLINICAL FEATURES
DIAGNOSTIC CRITERIA
Diagnosis of HFpEF requires that:
 Patient have signs and symptoms of heart failure
 An EF greater than 50%
 Objective evidence of cardiac dysfunction

FIGURE 27-7 Diagnostic criteria for HFpEF from the Heart Failure Society of America (HFSA) (left) and the European Society of Cardiology
(ESC) (right) guidelines.
 Clinical manifestations of heart failure are similar regardless of the EF
 These include reduced exercise tolerance, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, peripheral
edema, and pulmonary congestion apparent on chest radiographs
No clinical features (symptoms, signs, or chest radiography) can be used to reliably distinguish between HFpEF
and HFrEF
 In HFpEF the EF is not abnormal (i.e., EF >50%) and the end-diastolic volume is not increased, so an elevation of the
biomarker B-type natriuretic peptide (BNP) (or its N-terminal pro form), abnormal LV diastolic function (determined

Chapter 27: Heart Failure with a Preserved Ejection Fractions

noninvasively or by direct measurement of LV diastolic pressure), or elevated LA volume is required for the diagnosis of
HFpEF
 Diagnosis of HFpEF requires the exclusion of noncardiac causes of symptoms and signs
BIOMARKERS
Natriuretic peptides, BNP  Best-characterized biomarkers in patients with HFpEF
and N-terminal proBNP
(NT-proBNP)
 Patients with HFpEF, increased BNP is directly related to LV diastolic filling pressure and end-diastolic wall stress
 For any given LV diastolic filling pressure in patients with HFpEF, BNP levels are lower in obese patients and higher in
women, older persons, and patients with concomitant pulmonary disease (chronic obstructive disease, pulmonary
hypertension, and pulmonary embolus) and renal dysfunction
 Because patients with HFpEF have a smaller LV cavity and thicker LV walls, their end-diastolic wall stress is much lower
than in HFrEF, even in the setting of high systolic and diastolic pressures, thus producing a lower stimulus for BNP
production
 Patients with, HFpEF presenting with acute decompensation have:
 BNP value of 100 to 500 pg/mL, versus 500 to 1500 pg/mL in patients with HFrEF
 The standard partition values for BNP of 100 pg/mL and for NT-proBNP of 800 pg/mL have been suggested to
support the diagnosis of HFpEF
 Both baseline values and change from baseline predict cardiovascular outcomes in patients with HFpEF
 Elevation of BNP also indicates increased risk for subsequent events, even in asymptomatic persons

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FIGURE e27-2
A, Baseline values of NT-proBNP have significant prognostic value and predict morbidity and mortality outcomes. The higher the baseline
value of NT-proBNP, the higher the rate of the primary and heart failure endpoints in the I-Preserve study.
B, Change from baseline values of NT-proBNP have significant prognostic value and predict morbidity and mortality outcomes. Data from the
I-Preserve study indicated that the directional change in NT-proBNP predicted primary and heart failure outcome rates
DEMOGRAPHIC FEATURES
 Incidence of HFpEF increases with age, and the condition is more prevalent in women (may differ in specific populations)
 African Americans may develop HFpEF at a younger age
 Antecedent and co-morbid conditions are different in HFrEF versus HFpEF
 History of hypertension is present in a majority of patients with HFpEF (80% to 90%), and the disorder may have
developed only later in life
 Obesity is seen in 30% to 50%
 Diabetes in 20% to 30%
 Atrial fibrillation in up to 20% to 30% of patients
 Prevalence of renal disease is high, and it may be progressive
 Prevalence of coronary artery disease is 20% to 40%
 Presence of each of these co-morbid conditions predicts higher morbidity and mortality
 Medications used by patients with HFpEF and those with HFrEF are similar and include diuretics, digoxin, angiotensin
converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blocking agents, calcium channel blocking
agents, and various other vasodilators and antihypertensive and antiarrhythmic drugs

Chapter 27: Heart Failure with a Preserved Ejection Fractions

comorbid conditions
AGING  Incidence of HFpEF increases with age
 LV diastolic function becomes abnormal with normal aging
 Arterial, LV systolic, and LV diastolic stiffness increase with aging
 Structural cardiac changes with aging (e.g., increased cardiomyocyte size, increased apoptosis
with decreased cardiomyocyte number, altered growth factor regulation, and focal collagen
deposition) and functional changes at the cellular level involving blunted beta-adrenergic
responsiveness, excitation-contraction coupling, and altered calcium handling proteins also may
contribute to diastolic dysfunction with normal aging
 Some evidence suggests that prolonged, sustained endurance training may slow or prevent
some of the age-related changes
SEX  Female sex is a potent risk factor for HFpEF
 Women have more arterial and LV systolic and diastolic stiffness compared with men, and
arterial and ventricular stiffness increases more dramatically with age in women
HYPERTENSION  Most commonly associated cardiac condition in patients with HFpEF
 Chronically increased systolic blood pressure is an important stimulus for cardiac structural
remodeling and functional changes
 Resultant hypertensive heart disease is characterized by concentric remodeling or overt LV

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 hypertrophy, increasing arterial and ventricular systolic stiffness, impaired relaxation, and
increased diastolic stiffness—all factors linked to the pathogenesis of HFpEF
CORONARY ARTERY DISEASE
ATRIAL FIBRILLATION  Atrial fibrillation is recognized as a frequent precipitant of acute decompensation in patients
AND OTHER RHYTHM with HFpEF
DISTURBANCES  Due to the loss of atrial contraction and to the resulting tachycardia
 Atrial fibrillation may cause acute decompensation of heart failure in patients with diastolic
dysfunction, diastolic dysfunction (even in the absence of heart failure) results in left atrial
enlargement and increases the risk of atrial fibrillation
OBESITY  Associated with an increased risk for heart failure regardless of EF
 Patients with HFpEF are more often obese than patients with HFrEF
 Prevalence of diastolic dysfunction is increased in obese persons
 Increased body mass index (BMI) is a risk factor for hypertension, diabetes mellitus, coronary
artery disease, and atrial fibrillation
 Dramatic weight loss with caloric restriction or bariatric surgery is associated with improved LV
diastolic function
DIABETES MELLITUS  Potent risk factor for heart failure
 Prevalence is similar in patients with HFrEF and in those with HFpEF
 Morphologic changes in the diabetic heart include myocyte hypertrophy, increased
extracellular matrix (fibrosis), and intramyocardial microangiopath y
 Functional changes include impaired endothelium-dependent and endothelium-independent
vasodilation, impaired LV relaxation, increased passive diastolic stiffness, and contractile
dysfunction
 Mechanisms contributing to structural and functional coronary vascular and myocardial
changes include metabolic disturbances, activation of proinflammatory and profibrotic
mediators, cardiac autonomic neuropathy, and increases in advanced glycation end-products
(AGEs), which promote increased collagen accumulation and stiffness
CHRONIC KIDNEY DISEASE
SLEEP APNEA  Can contribute to symptom severity
 Likely to promote progression of heart failure
 Central sleep apnea can occur in association with severe HFpEF
PULMONARY  Most patients with HFpEF have at least some degree of pulmonary hypertension, with
HYPERTENSION pulmonary artery systolic pressures commonly greater than 40 mm Hg

Chapter 27: Heart Failure with a Preserved Ejection Fractions

 Partly a consequence of the elevated LV filling pressures, with resulting increased pulmonary
venous pressure
 Presence of increased pulmonary artery pressures has prognostic implications and is associated
with higher morbidity and mortality rates
RARER CAUSES OF HEART FAILURE WITH PRESERVED EJECTION FRACTION
 Hypertrophic cardiomyopathy
 Infiltrative cardiomyopathies such as amyloidosis , valvular disease, and constrictive pericarditis should always be
considered in patients with HFpEF
ACUTE DECOMPENSATED HEART FAILURE IN PATIENTS WITH HFPEF
 Majority of patients hospitalized for ADHF have preexisting heart failure; at least 50% of these patients have HFpEF
 Rehospitalizations are frequent, but many patients with HFpEF may be minimally symptomatic between episodes of ADHF
due to pulmonary congestion that accompanies increases in LV diastolic filling pressure
 Both baseline LV diastolic filling pressure and changes in filling pressure are sensitive predictors of future ADHF events
 ADHF in patients with HFpEF can result from increased filling pressure with or without significant changes in LV diastolic
volume
 In patients with HFpEF, arterial hypertension, myocardial ischemia, and diabetes mellitus can act on preexisting structural
and functional abnormalities to cause deterioration in LV diastolic function and precipitate ADHF.
 Atrial arrhythmias can result in loss of atrial function and stimulate compensatory increases in diastolic filling pressure in

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 order to maintain LV filling and maintain cardiac output
 Decreased LV diastolic function and abnormal LA function can result in neurohormonal activation, which plays an important
role in ADHF by producing increased sodium and water retention, increased venous return, increased splanchnic tone, and
arterial vasoconstriction
CLINICAL ASSESSMENT OF CARDIOVASCULAR STRUCTURE AND FUNCTION
LEFT VENTRICULAR STRUCTURE
LEFT VENTRICULAR VOLUME
 Most (>90%) patients with HFpEF have normal LV chamber dimension, area, and volume
 Up to 5% of patients have a mild increase in LV volume above the upper normal partition value of 75 mL/m
 LV volume less than 75 mL/m2 is one of the guidelines-based diagnostic criteria for HFpEF
LEFT VENTRICULAR MASS
 LV mass is increased and reaches criteria for LV hypertrophy in roughly 30% to 50% of patients with HFpEF
 Some evidence suggests that the prevalence of LV hypertrophy may be higher among African American patients and
women with HFpEF
 When present, LV hypertrophy is associated with significantly worse prognosis
LEFT VENTRICULAR GEOMETRY
 Ratio of LV mass to volume (M/V), or of LV wall thickness to LV internal dimension (relative wall thickness [RWT])
 When mass or thickness is increased relative to (or out of proportion with) volume or dimension, the resultant changes
are termed concentric remodeling
 Concentric remodelling can occur even in the absence of frank LV hypertrophy in approximately 20% to 30% of
patients with HFpEF and is associated with a 25% to 35% higher risk of heart failure events
LEFT VENTRICULAR FUNCTION
DIASTOLIC PROPERTIES

Chapter 27: Heart Failure with a Preserved Ejection Fractions

FIGURE 27-9 Evaluation of diastolic function based on the left ventricular filling dynamics determined by Doppler measurement of
mitral valve flow velocity and tissue Doppler measurement of mitral annular velocity
 Normally the early diastolic mitral flow velocity (E) and the mitral annular velocity (e′) are brisk and occur nearly simultaneously
 With mild diastolic dysfunction (impaired relaxation pattern—grade 1) the mitral E velocity is reduced and is less than the late
diastolic mitral flow velocity (A) The E deceleration time (DT) is increased
 With more severe diastolic dysfunction (grades 2 and 3), E is increased and the DT is reduced. In these patterns, e′ is reduced and
delayed relative to the mitral E.

DIASTOLIC FUNCTION GRADE

(Echocardiographic and Doppler-echo based grading scale)
Most common clinical method of assessing severity of diastolic dysfunction
GRADE
0 Normal
 Presence of mild diastolic dysfunction with slow LV relaxation
1 Abnormal  Early diastolic pressure gradient between the left ventricle and the left
relaxation atrium that accelerates transmitral flow into the left ventricle is decreased
because there is no increase in LA pressure, and early LV diastolic
pressure is higher owing to abnormal relaxation

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  Decrease in both the early transmitral flow velocity E and early tissue
velocity, e', and an increase in the importance of late diastolic mitral flow
velocity (A), the transmitral velocity resulting from atrial contraction,
producing an E/A ratio less than 1
 Occurs when progressive worsening of diastolic dysfunction is associated
with an increase in LA pressure and there is restoration of the early
diastolic pressure gradient despite increased early diastolic LV pressures.
These changes result in a return of the E wave to the normal range
2 Pseudonormalized (pseudonormal mitral inflow pattern)
 Displacement of the left ventricle onto a steeper portion of the pressure-
volume curve results in a shortening of the DT
 With slower relaxation, the e′ is delayed, occurring after the E
 Indicates that the left ventricle is not expanding symmetrically in
diastole, but that propagation of filling to the apex and longitudinal
expansion occurs slowly after the left ventricle is filled by the movement
of blood from the left atrium into the LV inflow tract
 Pseudonormal mitral inflow pattern is distinguished from normal by a reduced and delayed e′ and increase in the E/e′
ratio
3a Reversible restrictive  Occurs when severe diastolic dysfunction causes a markedly slowed
3b Irreversible relaxation and elevated LA pressure
restrictive  E increases further, DT becomes very short, and e′ is further reduced and
delayed resulting in a marked elevation of E/e′
 Late diastolic annular velocity (a′) also may be reduced, and pulmonary
venous systolic forward flow velocity is reduced as well, to less than
diastolic forward flow velocity
 If a Valsalva maneuver causes a reduction of E wave velocity, the
condition is designated reversible
 If Valsalva does not change E, it is designated irreversible
NONINVASIVE ESTIMATION OF LEFT VENTRICULAR DIASTOLIC FILLING PRESSURE
 Pseudonormalized and restricted filling patterns indicate the presence of both diastolic dysfunction and elevated LA
pressure
 Impaired relaxation pattern indicates diastolic dysfunction without a marked elevation in LA pressure

Chapter 27: Heart Failure with a Preserved Ejection Fractions

 Additional echo Doppler measurements that may reflect diastolic filling pressures include estimation of peak RV systolic
pressure (PRVSP) from the tricuspid regurgitation velocity and LA volume
 Most common cause of increased pulmonary artery systolic pressure in HFpEF is an elevation of LA pressure
 Echocardiographic parameters best correlated with PRVSP are DT and E/e′
 Changes in LA volume reflect longer-term changes in LV filling pressures
 LA volume is dependent on the product of diastolic pressure and time, so the longer pressures are increased and the
higher they are increased, the larger the LA volume
 Abnormal diastolic dysfunction grade, increased PRVSP, and increased LA volume are highly prevalent in patients with
HFpEF and have significant prognostic value
See FIGURE 27-10 Prognostic significance of alterations in cardiac structure and function in patients with HFpEF. Left atrial enlargement (A),
diastolic dysfunction grade (B), and LV hypertrophy (C) increased the risk of primary and heart failure endpoints in the I-Preserve study
 Most commonly used and easily interpretable parameter to estimate LA pressure is the E/e′ ratio
 E/e′ has been found to correlate with pulmonary capillary wedge pressures (PCWPs)
 E/e′ greater than 15 has been found to clearly indicate elevated PCWP
 E/e′ less than 8 is associated with normal LA pressure
 Cut-off value of E/e′ of 15 to recognize elevated LA pressure was obtained using e′ velocity from the medial mitral
annulus
 Because e′ velocity from the lateral annulus usually is higher than the medial e′ velocity, the cut-off value should be
adjusted to 12 if the lateral annular velocity is used
Limitations in Use of E/e (see page 674 ebook)
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1.In a normal heart, e′ occurs coincidentally with E and responds to changes in LA pressure
2.E/e′ does not increase in patients with constrictive pericarditis despite elevated PCWPs
 Median e′ increases as constriction becomes worse, which results in a decrease in E/e′ as constriction gets more severe
and diastolic filling pressure increases (annulus paradoxus)
 If the patient has clinical signs of heart failure, especially with increased jugular venous pressure, a normal or increased
median e′ velocity strongly suggests constrictive pericarditis
3.E/e′ may not provide an estimate of LA pressure in patients with mitral stenosis or mitral regurgitation, especially without a
reduction in EF
4.Although E/e′ correlates with LA pressure in patients with hypertrophic cardiomyopathy, the substantial scatter of data limits
its use alone in an individual patient
PREVALENCE AND PROGNOSIS FOR DIASTOLIC DYSFUNCTION IN HFPEF
 Stage of diastolic dysfunction correlates with the impairment of exercise capacity in patients without myocardial ischemia,
whereas LV EF does not
 In patients with heart failure, the stage of diastolic dysfunction is a stronger predictor of mortality than
EF
 Indicates an increased LV operating stiffness
SHORT DT  Hallmark of restrictive filling pattern
 Connotes poor prognosis in patients with a history of myocardial infarction, persons with dilated
cardiomyopathy, heart transplant recipients, and patients with hypertrophic or restrictive
cardiomyopathy
 Both pseudonormalized and restricted filling patterns are associated with a four-fold increase in the risk of death in patients
with heart failure and coronary artery disease
 Patients with HFpEF, abnormal diastolic function measured as diastolic dysfunction grade or LA enlargement also predicts
marked increase in morbidity and mortality events
SYSTOLIC PROPERTIES
 Patients with HFpEF have a normal (or near-normal) EF
 Patients with HFpEF have normal dP/ dtmax, stoke volume, stroke work, and preload recruitable stroke work
 Indices of chamber contractility such as LV end-systolic elastance are actually increased in HFpEF, matching the increased
arterial elastance, so that the coupling between these properties is preserved
 Because systolic and arterial elastances are increased in HFpEF, exercise-induced increases in RAAS and sympathetic
stimulation are unable to augment systolic properties sufficiently to maintain adequate stroke volume
THERAPY

Chapter 27: Heart Failure with a Preserved Ejection Fractions

“No treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF”

SUMMARY RANDOMIZED CONTROLLED TRIALS

Digitalis Investigators Group
(DIG) Trial
Candesartan in Heart Failure:
Assessment of Reduction in
Mortality and Morbidity
(CHARM)
 988 patients with ambulatory HFpEF (EF >45%) in normal sinus rhythm
 Digoxin did not alter the primary endpoint of heart failure-–related hospitalization
or cardiovascular mortality but did reduce the number of such hospitalizations
 Total cardiovascular hospitalizations were not reduced, however, because of an
increased rate of admissions for unstable angina, which completely negated the
benefit of reduced heart failure hospitalizations
 Evaluated the ARB candesartan in patients with heart failure
 In the CHARM Preserved arm, patients with heart failure and an EF above 40%
were randomly assigned to receive candesartan or placebo in addition to standard
therapy
 Fewer patients in the candesartan group than in the placebo group reached the
primary endpoint of cardiovascular death or heart failure–related hospitalization, a
finding that reached statistical significance only after adjustment for small
differences in baseline characteristics
 Furthermore, there was no impact on mortality

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Perindopril in Elderly People
with Chronic Heart Failure
(PEP-CHF) trial
Irbesartan in Heart Failure with
Preserved Ejection Fraction
Study (I-Preserve)
Study of the Effects of
Nebivolol Intervention on
Outcomes and
Rehospitalization in Seniors
with Heart Failure (SENIORS)
trial
Phase II Studies of Novel Pharmacologic Treatment of HFpEF
Prospective comparison of ARNI
versus ARB on Management of
Heart Failure with Preserved
Ejection Fraction
(PARAMOUNT)
RELAX trial
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 Older than 70 years of age with HFpEF (EF >0.45) with echocardiographic evidence
of diastolic dysfunction
 Randomly assigned to receive perindopril (an ACE inhibitor) or placebo
 Primary endpoint was a composite of all-cause mortality or unplanned heart
failure–related hospitalization
 Both enrolment and event rates were lower than anticipated, and a high rate of
cessation of blinded therapy, with crossover to open-label ACE inhibitor use, was
reported for both groups.
 These factors limited the power of the study, which did not show significant
reduction in the primary endpoint
 Some trends toward benefit, primarily driven by reduction in heart failure–related
hospitalizations, were observed in a post hoc analysis of the results at 1 year, when
crossover therapy rates were lower
 Tested the ARB irbesartan in 4128 patients who were at least 60 years of age and
had New York Heart Association (NYHA) class II, III, or IV heart failure, with an EF
above 45%
 Primary outcome was death from any cause or hospitalization for a cardiovascular
cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke)
 Secondary outcomes included death from heart failure or hospitalization for heart
failure, death from any cause and from cardiovascular causes, and impaired quality
of life.
 Irbesartan had no effect on any of the prespecified outcomes
 Tested the effect of the beta1-selective blocking agent nebivolol in patients
with heart failure without an EF requirement
 Modest but significant reduction was observed in the primary endpoint of all-cause
mortality or cardiovascular hospitalizations, driven primarily by the effect on
hospitalizations
 Prespecified subgroup analysis in patients with EF above versus below 35% did not
detect any trends toward reduced benefit in those with higher EF very few patients
with EF above 50% were included in the trial
 Thus it is not possible to draw conclusions about the benefit of beta blocking agents
in HFpEF from this study
 Analysis of a large observational study found no mortality benefit of treatment with
a beta blocking agent after a hospitalization for heart failure in patients with EF
Chapter 27: Heart Failure with a Preserved Ejection Fractions
above 40%
 Patients with NYHA class II or III HFpEF (EF >45%) and NT-proBNP level greater than
400 pg/mL
 Cohort of 149 patients were assigned to receive therapy with LCZ696 (200 mg twice
daily) and another 152 patients to receive valsartan (160 mg twice daily) for 36
weeks
 Primary endpoint was change in NT-proBNP from baseline to 12 weeks
 At 12 weeks, LCZ696 significantly reduced NT-proBNP by approximately 15%,
compared with valsartan (no significant change; for difference in response, P = .005)
 At 36 weeks, LCZ696 significantly reduced LA volume by approximately 5%
compared with valsartan (no significant change; for difference in response, P = .003)
 LCZ improved NHYA functional class versus valsartan (P = .05)
 LCZ696 was well tolerated, with adverse effects similar to those for valsartan.
 Whether these findings will translate into improved outcomes need to be tested in a
large randomized trial
 Sildenafil was studied in a larger group of patients with HFpEF without a requirement
for having pulmonary hypertension, no improvement was observed in exercise
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 tolerance or diastolic function
 To date, spironolactone has been shown to improve indices of diastolic function but not clinical outcomes
MANAGEMENT OF HEART FAILURE WITH PRESERVED EJECTION FRACTION 
Three main components
Reduction and prevention of  Fluid and sodium restriction, judicious use of diuretics and nitrates, selective
pulmonary and peripheral venous application of neurohormonal modulation, and appropriate remote monitoring–
congestion based tailored care
Aggressive treatment of antecedent  Controlling blood pressure at rest and modifying blood pressure response to
and comorbid diseases exercise, controlling glucose, treating and preventing ischemia, and maintaining
adequate renal function
Optimization of cardiac functional  Prevent excessive tachycardia or bradycardia, to match heart rate to metabolic
status needs, to maintain or restore normal sinus rhythm, and to control ventricular
response rate during atrial arrhythmias
NONPHARMACOLOGIC THERAPY
 Attention to diet and lifestyle, avoidance or reversal of obesity, increase in exercise, adherence to management strategies,
daily monitoring of weight, patient education, and close medical follow-up using facilitated home management
 Sodium restriction to less than 2 g/day may be effective
TREATMENT OF COMORBID CONDITIONS
 Most important and frequent comorbid conditions include arterial hypertension, obesity, diabetes, chronic kidney disease,
obstructive sleep apnea, and anemia
 Most patients (>85%) with HFpEF have either current or previous hypertension
 Untreated hypertension is a strong risk factor for the development of heart failure
 Treatment of systolic hypertension in elderly patients (who have the highest risk for development of HFpEF) is associated
with a more than 50% reduction in the frequency of heart failure
 Goal of therapy is systolic arterial pressure below 140 mm Hg and diastolic blood pressure below 90 mm Hg
 GFR is an important predictor of outcomes in patients with HFpEF, with decreasing estimated GFR predicting increased
event rates
 Anemia is common in HFpEF and is associated with a worse prognosis
PHARMACOLOGIC AND DEVICE-BASED STRATEGIES
 Prospective RCTs have evaluated the efficacy of digitalis, ACE inhibitors, ARBs, and beta blocking agents in patients with
HFpEF; each of these studies found no clear benefit to these therapies
 RAAS antagonism is thus an important component of treatment in patients with HFpEF, particularly to manage hypertension,
prevent or reverse LV hypertrophy, and preserve renal function in patients with diabetes
REMOTE MONITORING SYSTEMS TO HELP TAILOR MANAGEMENT
Chronicle Offers Management to  70 patients with HFpEF (with EF >50%) were studied using an implantable

Chapter 27: Heart Failure with a Preserved Ejection Fractions

Patients with Advanced Signs hemodynamic monitor (IHM) that measured an estimated pulmonary artery diastolic
and Symptoms of Heart Failure pressure (ePAD)
(Compass-HF) trial  Measurement that in the absence of pulmonary vascular disease approximates
PCWP
 This study demonstrated that:
(1) patients with HFpEF demonstrated significantly increased filling pressures even
while they were considered to be in a compensated state by their physicians;
(2) these pressures rose further when they became decompensated
(3) both baseline pressures and change from baseline pressures predicted outcomes
CardioMEMS Heart Sensor Allows  Those in the active treatment arm demonstrated a 152% decrease in pulmonary
Monitoring of Pressure to Improve artery diastolic and systolic pressures and a 52% decrease in heart failure– related
Outcomes in NYHA class III Heart events (both P < .0001 and control)
Failure Patients (CHAMPION) trial
Left Atrial Pressure Monitoring to
Optimize Heart Failure Therapy
(LAPTOP-HF) trial
Repeated measurements of biomarkers, both office- and home-based, are being evaluated. These include use of BNP (HABIT-I
and -II study) and galectin (REGAL-HF study)

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 NEUROHORMONAL MODULATION
Aggressive and effective management of hypertension is an essential component of treatment in HFpEF
Complete management of HFpEF includes the prevention of the development of LV hypertrophy or the induction of its
regression.

ACC/AHA GUIDELINES

Systolic and diastolic blood pressure should be controlled in patients with 2013 recommendation remains
I B HFpEF in accordance with published clinical practice guidelines to prevent current.
morbidity

Diuretics should be used for relief of symptoms due to volume overload in 2013 recommendation remains
I C
patients with HFpEF. current.

Coronary revascularization is reasonable in patients with CAD in whom 2013 recommendation remains
IIa C symptoms (angina) or demonstrable myocardial ischemia is judged to be current.
having an adverse effect on symptomatic HFpEF despite GDMT.

Management of AF according to published clinical practice guidelines in 2013 recommendation remains

IIa C
patients with HFpEF is reasonable to improve symptomatic HF. current.

The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with 2013 recommendation remains
IIa C
hypertension is reasonable to control blood pressure in patients with HFpEF. current.

In appropriately selected patients with HFpEF (with EF ≥45%, elevated BNP NEW: Current recommendation
levels or HF admission within 1 year, estimated glomerular filtration rate >30 reflects new RCT data.
IIb B-R
mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L), aldosterone receptor
antagonists might be considered to decrease hospitalizations.

The use of ARBs might be considered to decrease hospitalizations for patients 2013 recommendation remains
IIb B
with HFpEF. current.

Chapter 27: Heart Failure with a Preserved Ejection Fractions

III: No Routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity NEW: Current recommendation
B-R
Benefit or QoL in patients with HFpEF is ineffective. reflects new data from RCTs.

III: No Routine use of nutritional supplements is not recommended for patients with 2013 recommendation remains
C
Benefit HFpEF. current.

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