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RE VIE W

Heart Failure with Preserved Ejection Fraction:Pathophysiology and Emerging Therapies

Aaron M. From & Barry A. Borlaug

Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, MN, USA

Keywords

Diastole; Heart failure; Heart failure with

preserved ejection fraction; Hypertension;

Pathophysiology; Treatment.

Correspondence

Barry A. Borlaug, M.D., Mayo Clinic, 200 First

Street SW, Rochester 55905, MN, USA.

Tel: 507-284-4442;Fax: 507-255-2550;

E-mail: [email protected]

doi: 10.1111/j.1755-5922.2010.00133.x

Approximately half of patients with heart failure (HF) have a preserved ejec-

tion fraction (HFpEF). Morbidity and mortality are similar to HF with reduced

EF (HFrEF), yet therapies with unequivocal benefit in HFrEF have not been

shown to be effective in HFpEF. Recent studies have shown that the patho-

physiology of HFpEF, initially believed to be due principally to diastolic dys-

function, is more complex. Appreciation of this complexity has shed new light

into how HFpEF patients might respond to traditional HF treatments, while

also suggesting new applications for novel therapies and strategies. In this re-view, we shall briefly review the pathophysiologic mechanisms in HFpEF, cur-

rently available clinical trial data, and finally explore new investigational ther-

apies that are being developed and tested in ongoing and forthcoming trials.

Introduction

Approximately half of patients with heart failure (HF)

have a preserved ejection fraction (HFpEF) [1]. Morbidity

and mortality are similar to HF with reduced EF (HFrEF)

[1,2], yet therapies with unequivocal benefit in HFrEF

have not been shown to be effective in HFpEF [35]. Re-

cent studies have shown that the pathophysiology of HF-

pEF, initially believed to be due principally to diastolic

dysfunction [610], is more complex [1124]. Apprecia-

tion of this complexity has shed new light into how HF-

pEF patients might respond to traditional HF treatments,

while also suggesting new applications for novel therapies

and strategies. In this review, we shall briefly review the

pathophysiologic mechanisms in HFpEF, currently avail-able clinical trial data, and finally explore new investi-

gational therapies that are being developed and tested in

ongoing and forthcoming trials.

Pathophysiology of HFpEF

Recent studies have substantially improved our under-

standing of pathophysiology in HFpEF. Table 1 describes

the central mechanisms described to date, their hemody-

namic effects and how they are believed to contribute to

clinical behavior and symptoms in HFpEF.

Diastolic Dysfunction

Diastolic dysfunction is characterized by impairments in

ventricular relaxation and chamber stiffness during filling

[610]. Abnormalities in each have been well described

in patients with HFpEF, though diastolic dysfunction is

often present in asymptomatic patients without HF, par-

ticularly with normal aging, hypertension and in the set-

ting of concentric ventricular remodeling [25]. The ma-

jority of patients with HFpEF and diastolic dysfunction

have a history of hypertension [10,17,26], and it is spec-

ulated that changes in ventricular structure and func-

tion in response to the latter create the substrate upon

which HFpEF is formed [10,22]. As patients with hyper-

tensive heart disease acquire additional abnormalities in

ventricular-vascular function (discussed subsequently),

there may be transition from the asymptomatic pa-

tient (ACC/AHA Stage B) to symptomatic heart failure

(Stage C) [27]. It is widely [8,9] though not universally

e6 Cardiovascular Therapeutics 29 (2011) e6e21 c 2010 Blackwell Publishing Ltd


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A.M. From and B.A. Borlaug Heart Failure with Preserved Ejection Fraction

Table 1 Pathophysiologic mechanisms of heart failure with preserved ejection fraction

Mechanism Hemodynamic effects Clinical sequelae References

Ventricular diastolic

dysfunction

1. LV relaxation rate and

diastolic stiffness lead to LV

filling pressures

Dyspnea at rest or exertion

Pulmonary congestion/edema

Fatigue/effort intolerance

Kitzman [6], Gandhi [7], Zile [8],

Lam [10], Westermann [9], Phan [24],

Tan [23], Chatto-hadpyay [42]

2. Secondary pulmonary

hypertension

Systemic edema and congestion

3. FrankStarling reserve with

exercise

Ventricular systolic

dysfunction

1. Minimal effects at rest

2. Contractile reserve with

exercise:

Minimal sequelae at rest



Liu [47], Yip [12], Yu [13], Petrie [14],

Borlaug [15, 22, 40], Ennezat [19],

Tan [23], Phan [24],

a. Stroke volume reserve

b. LV end systolic volume with

exercise may diastolic reserve

Ventricular systolic

stiffening

1. Changes in blood pressure

with alterations in preload or

afterload

Hypotension and oliguria with

slight overdiuresis or addition of

a new vasodilator

Chen [51], Kawaguchi [11], Borlaug

[22,39], Lam [10]

2. Contractile and stroke volumereserve with exercise

Hypertensive crisisPulmonary congestion/edema

3. LV work required to eject given

stroke volume


Myocardial oxygen demand with

ischemia/angina

Vascular stiffening and

dysfunction

1. LV afterload-stroke volume

reserve

2. LV relaxation due to #1

Hypertensive response to exercise



Kawaguchi [11], Hundley [52], Borlaug

[15, 30, 39, 50], Ennezat [19],

Leite-Moreira [31,32],

3. Exercise vasodilation

4. Endothelial Dysfunction

Myocardial oxygen demand with

ischemia/angina

Neuro-hormonal

activation

1. Extracellular fluid volume

2. Cardiac filling volumes and

consequent filling pressures



Fatigue/fffort intoleranceSystemic edema/congestion

Maurer [16, 18], Kitzman [119],

Abramov [68]

Left atrial dysfunction 1.Atrial contractility and atrial

contractile reserve

2. Atrial remodeling



Atrial fibrillation

Melenovsky [17], Gottdiener [54]

Fung [55]

Pulmonary hypertension 1.Right ventricular afterload Dyspnea at rest or exertion Klapholz [26], Lam [21], Kjaergaard [56]

2. RV stroke volume reserve Fatigue/effort intolerance

3. RV remodeling Systemic edema/congestion

Autonomic dysfunction 1. Chronotropic incompetence Exert ional dyspnea Borlaug [15], Brubaker [41]

2. Sympathetic hyperactivation Effort intolerance and fatigue Kasama [44], Phan [45]

Skeletal muscle

dysfunction1. Impaired vasodilation

2. Sympathetic hyper-activation

and ergoreflex stimulation

Muscle wasting

Exertional dyspnea

Effort intolerance and fatigue

Clark [65]

Witte [64]

Anemia 1. Cardiac output to maintain

oxygen delivery

Exertional dyspnea

Effort intolerance and fatigue

Felker [69], Latado [71]

Abramov [68]

2. Viscosity Angina/ischemia Groenveld [70]

Described in HFrEF and presumed to contribute to HFpEF but not described.

Cardiovascular Therapeutics 29 (2011) e6e21 c 2010 Blackwell Publishing Ltd e7


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Heart Failure with Preserved Ejection Fraction A.M. From and B.A. Borlaug

[28] believed that diastolic dysfunction lies at the center

of the process, though it is now clear that multiple nondi-

astolic abnormalities also contribute. When younger pa-

tients present with HFpEF, particularly in the absence of

a history of hypertension, hypertrophic, restrictive, or in-

filtrative cardiomyopathy should be suspected [16]. These

patients tend to display the most dramatic extremes of di-astolic dysfunction and can be very difficult to treat.

Diastolic dysfunction may be due to processes oper-

ating at the level of the sarcomere, myocyte, extracel-

lular matrix, and chamber, each of which represents a

potential therapeutic targetthese processes have been

reviewed in detail elsewhere [25]. Despite a wide array

of potential targets, there are no currently approved oral

therapies that directly treat diastolic dysfunction. There

is substantial evidence that elevated afterload impairs di-

astolic function, suggesting that vasodilators may indi-

rectly treat diastolic abnormalities [2934]. Inotropes en-

hance diastolic relaxation directly by affecting calcium

handling and sarcomeric thickthin filament interaction,

and indirectly by decreasing ventricular end-systolic vol-

ume, which increases elastic recoil during early diastole

[25,35], but currently available inotropes increase mor-

tality in HFrEF and have no role in the treatment of HF-

pEF [27]. Because diastolic dysfunction is felt to result

largely from maladaptive ventricular remodeling, ther-

apies which treat this remodeling may improve dias-

tolic dysfunction or prevent/delay its development [25].

Investigational therapies directly targeting diastolic dys-

function are discussed further.

Systolic Dysfunction

Ejection fraction is normal or near-normal in HFpEF,

both at rest and during acute pulmonary edema [7], but

EF in itself is not a robust measure of contractility. At the

same contractility level, EF tends to increase slightly with

increases in preload, while it decreases markedly with

acute elevations in afterload [36]. Numerous studies have

shown that measures of regional systolic function, most

frequently measured by Tissue-Doppler or strain echocar-

diography, are depressed in HFpEF [1214,17,37,38]. Ab-

normal myocardial shortening or thickening has been

shown principally in the longitudinal axis, but recently

abnormalities in radial deformation, twist and untwist

have been observed [20,23]. Because diastolic filling is

enhanced by ventricular untwisting or recoil during early

diastole, systolic dysfunction may promote diastolic dys-

function via this cross talk [35,39]. Similar to EF, these

regional measures of systolic shortening or thickening,

vary inversely with afterload [30], which is often ele-

vated in HFpEF, suggesting that part of this abnormality

may be related to chronic increases in ventricular load.

Using load-independent measures, Baicu et al. found no

difference in global chamber systolic function compar-

ing HFpEF patients to healthy controls [38]. More re-

cently, a larger-sized, population-based study found that

despite preservation of EF, chamber-level and myocardial

contractility are subtly but significantly depressed in HF-

pEF, and intriguingly, more severe contractile dysfunc-tion in HFpEF was shown to predict increased mortality

[22]. Whether or how mild systolic dysfunction in HFpEF

should be treated remains unclear, but as discussed sub-

sequently, even mild deficits in resting systolic function

may become extremely limiting under stress conditions,

such as with exercise [15,19,23,24,40,41].

Cardiovascular Reserve Function in HFpEF

The majority of earlier mechanistic studies focused on

measuring indices of cardiovascular function under rest-

ing conditions. However, most patients with HFpEF com-

plain of symptoms predominantly during exercise [26].

A number of recent studies have highlighted the impor-

tance of abnormalities in ventricular-vascular reserve in

HFpEF, defined by the change in a given measure of

cardiovascular function with stress [6,19,23,24,4042].

Kitzman et al. showed that diastolic reserve function is

blunted in HFpEFpatients displayed less increase in

ventricular preload (end-diastolic volume) with exercise

than controls, despite marked elevations in ventricu-

lar filling pressures [6]. However, this study was small

(n =7) and nearly half of the subjects had hypertrophic

or infiltrative cardiomyopathydiseases known to pro-

duce the most dramatic extremes of diastolic dysfunction.These results may be less relevant to patients with di-

astolic dysfunction related to hypertensive heart disease.

Recent studies have confirmed greater increases in dias-

tolic pressures with exercise in HFpEF, though intrigu-

ingly, acute exercise changes in diastolic relaxation and

stiffness were no different than those observed in con-

trols [9]. A recent tissue-Doppler study noted impaired

enhancement in early relaxation (E velocity) with dobu-

tamine stimulation in HFpEF, consistent with impaired

lusitropic reserve [42].

In addition to diastolic reserve dysfunction, there are

commonly abnormalities in systolic responses to exercise

in HFpEF. Brubaker et al. and Borlaug et al. first showed

that chronotropic reserve is depressed in HFpEF, and

that this impairment is strongly associated with reduced

exercise capacity [15,41]. The cause for chronotropic in-

competence is unknown and may be due to abnormali-

ties in -adrenergic signaling [43] or to autonomic dys-

function, as these patients have also been shown to

display reduced heart rate recovery, abnormal baroreflex

sensitivity and enhanced cardiac sympathetic stimulation



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[15,44]. Chronotropic incompetence in HFpEF has been

verified in several subsequent exercise studies [24,40,45],

challenging the conventional belief that heart rate slow-

ing with pharmacotherapy is universally indicated in HF-

pEF. Therapies such as cardiac pacing are currently being

investigated in HFpEF and will be discussed subsequently.

Enhancement of contractility during exercise is alsoimpaired in HFpEF [15,19,23,24,40]. This may be re-

lated to subtle resting contractile dysfunction, abnor-

mal calcium handling, passive stiffening, ischemia, ox-

idative stress, or abnormal myocardial energeticseach

of which may serve as a potential treatment target

[22,24,46,47]. In addition, normal exercise-induced re-

duction in vascular resistance is attenuated in HFpEF,

impairing cardiac output reserve, contributing to hyper-

tensive responses to exercise and leading to abnormal

dynamic ventriculararterial coupling [15,19,39,40]. Ab-

normal vasodilation may be related to endothelial dys-

function, which is well-described in HFrEF [48]. Though

an initial study did not demonstrate abnormal flow-

mediated vasodilation in HFpEF [49], a more recent study

did show endothelial dysfunction in this group, and in-

triguingly, the extent of dysfunction was associated with

both lower exercise capacity and greater symptoms of

dyspnea and fatigue, suggesting that therapies target-

ing endothelial dysfunction may prove useful in HFpEF

[50].

VentricularArterial Stiffening

Arterial hypertension is almost universal in elderly pa-

tients with HFpEF [10,26], and this is related to bothventricular and vascular stiffening [39,51]. Increased di-

astolic stiffness contributes to elevated filling pressures

at rest and with exercise, leading to dyspnea [6,8,9]. In-

creased systolic stiffness is also present in HFpEF [11], de-

spite impaired chamber and myocardial contractility [22].

Ventricular-arterial coupling, defined by the ratio of ar-

terial to ventricular systolic stiffness (elastance), is sim-

ilar in HFpEF, healthy controls, and asymptomatic hy-

pertensives [22]. However, while the coupling ratio is

preserved in HFpEF, its individual components (ven-

tricular and arterial stiffness) are similarly and markedly

elevated. This causes greater increases in blood pressure,

cardiac work, and oxygen demand to deliver a given

stroke volume, limiting exercise capacity, and causing

more dramatic fluctuations in systemic pressures with

changes in preload and afterload [11,39,52]. Because

of increased systolic ventricular stiffening (steep end-

systolic pressurevolume relationship), the patient with

HFpEF develops much more dramatic shifts in blood pres-

sure with vasodilation or vasoconstriction [11]. The clin-

ical correlate of this observation is that HFpEF patients

may be more prone to hypotension with overly aggres-

sive diuresis or vasodilation. Alternatively, such patients

are also likely to develop hypertensive crisis and/or acute

pulmonary edema with dietary or medication nonad-

herence. The effects of ventricular-vascular stiffening on

hemodynamics and clinical behavior in HFpEF have been

reviewed in detail elsewhere [39].

Other Mechanisms

Recent data has demonstrated primary abnormalities

in volume handling [16,18,53], left atrial function

[17,54,55], pulmonary hypertension [21,26,56], auto-

nomic dysfunction [15,44,45] and ventricular dyssyn-

chrony [57,58] in HFpEF. Data from the Cardiovascular

Health Study showed that patients with HFpEF on av-

erage display increased ventricular diastolic dimensions

[18]. Earlier studies from this group similarly showed

larger chamber volumes by 3D echo, combined with in-

creases in extracellular fluid volumesuggesting that fill-

ing pressures may be elevated in HFpEF primarily to

overfilling of the ventricle, rather than to an abnor-

mally stiffened ventricle [16]. Other studies have not cor-

roborated these findings [10,17,38], and further work is

required to clarify this question. Left atrial function is im-

paired in HFpEF [17,54], but it remains unknown how

this could be exploited therapeutically or whether any

such treatment would translate to clinical benefit. Pul-

monary hypertension is very common in HFpEF, being

present in 80% of patients, and its presence and sever-

ity predict increased mortality [21,56]. Intriguingly, el-

derly patients presenting the pulmonary hypertension byecho are more frequently found to display elevated left

ventricular filling pressures at catheterization, suggest-

ing that many of these patients in fact have HFpEF [59].

Pulmonary-specific vasodilators have failed to show ben-

efit in HFrEF and can in some patients exacerbate pul-

monary venous hypertension [60]. Recently completed

[61] and ongoing studies [62] are examining the role for

pulmonary vasodilators in HFpEF. As in HFrEF, there is

evidence that both systolic and diastolic dyssynchrony ex-

ist in HFpEF [57,58], but the extent to which these ab-

normalities contribute to pathophysiology in HFpEF is

unknown, and it is further unclear whether this sort of

heterogeneous dyssynchrony could even be resynchro-

nized [63].

A number of noncardiovascular mechanisms also con-

tribute to the pathophysiology in chronic HF. Decondi-

tioning is common, as patients withdraw from previously

more-active active lifestyles, and pulmonary abnormali-

ties are frequently observed [64]. Qualitative and quanti-

tative abnormalities in skeletal muscle function are well-

described in HFrEF, contributing to symptoms of exercise



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intolerance and dyspnea, while also exacerbating sym-

pathetic hyper-activation through ergoreflex stimulation

[6466]. While the latter mechanisms have not yet been

described in HFpEF, it is highly likely that they also play

important roles in contributing to symptoms of exertional

dyspnea and fatigue. Anemia and renal disease are well-

described comorbidities in HF regardless of EF, and whileeach is associated with increased mortality, it remains un-

clear whether or how treating these comorbidities might

improve outcome [6771].

HFpEF or Noncardiac Dyspnea?

Symptoms of exercise intolerance and exertional dyspnea

are highly sensitive for HF [72], but they are also very

nonspecific and may be attributable to a variety of non-

cardiac problems [7376]. As such, a number of inves-

tigators have appropriately emphasized that HFpEF may

be over-diagnosed in practice and in patients enrolled intrials [7375]. Caruana et al. reported that the vast ma-

jority of patients in their series of HFpEF had at least one

alternative explanation for symptoms, such as obesity or

lung disease [73]. However, multiple causes for dysp-

nea (e.g., obesity, COPD, HFpEF) may coexist within the

same patient [77], and the presence of one source does

not exclude another. Biomarkers such as brain natriuretic

peptide (BNP and NT-proBNP) have emerged as valuable

noninvasive surrogates of elevated filling pressures and

diastolic dysfunction in HFpEF [78]. Ingle et al. recently

reported that while patients with HFpEF have similar ob-

jective and subjective exercise limitation as those with

HFrEF, their BNP levels were no different than normal

controls, suggesting that exertional symptoms may not be

due to heart failure [76]. Elevated natriuretic peptide lev-

els predict increased risk for heart failure morbidity andmortality [75], but they are also known to be lower on

average in HFpEF than HFrEF [79], and the absence of

BNP elevation does not necessarily exclude the diagnosis

of invasively confirmed HFpEF [80]. Even after a consid-

erable battery of invasive and noninvasive evaluations,

the diagnosis of HFpEF may still remain unclear in many

cases, and until more gold standard diagnostic tests and

algorithms are validated, this uncertainty must be born

in mind when evaluating patients with normal EF and

dyspnea and considering the various treatment strategies

described further.

Conventional HF Therapies:What Is the Evidence?

In contrast to HFrEF, outcome data from random-

ized trials in HFpEF had been lacking for some time,

though recent large trials have shed important new light

(Table 2). There are many reasons for the relative paucity

of data in HFpEFincluding limited appreciation of the

scope of the HFpEF epidemic, problems with accuracy

Table 2 Randomized controlled trials in heart failure with preserved ejection fraction

Trial Drug Inclusion criteria N Follow-up Results

ACE-I/ARB

PEP-CHF [4] Perindopril 70 years, HF, EF 40% 850 2.1 years 1 endpoint (death or HF hospitalization)

Death

HF hospitalization

Symptoms

Exercise capacity

CHARM-Preserved [3] Candesartan HF & EF> 40% 3023 37 months 1 Endpoint (CV death or HF hospitalization)

Death

HF hospitalization

I-PRESERVE [5] Irbesartan HF and EF> 45% 4128 4 years 1 endpoint (death or CV hospitalization)

Death

HF hospitalization

Beta blockers

Aronow et al. [91] Propranolol Post-MI, HF, EF 40% 158 12 months death

EF

LV mass

Digoxin

Ancillary DIG [108] Digoxin HF and EF> 45% 988 37 months 1 endpoint (HF death or HF hospitalization)

Death

Hospitalization



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of diagnosis, difficulties enrolling HFpEF patients, who

are frequently older and have many comorbidities caus-

ing exclusion from trials, and the recent observation of

the importance of noncardiac complications in HFpEF pa-

tients, which importantly drive re-hospitalization rates

and overall mortality [81,82].

Angiotensin Converting Inhibitorsand Angiotensin Receptor Blockers

Medications that regulate the renin angiotensin system

are the best studied in hypertensive diastolic dysfunction

and HFpEF. Klingbeil et al. found in a meta-analysis of

hypertensive trials that LV mass was reduced most ef-

fectively by Angiotensin Receptor Blockers (ARBs) and

calcium channel blockers and least by -blockers and di-

uretics [83]. Little et al. showed in a study of 40 patients

with diastolic dysfunction and exercise-induced hyper-

tension that losartan blunted this hypertensive response

and resulted in improved exercise tolerance compared to

hydrochlorothiazide [84]. The Valsartan in Diastolic Dys-

function (VALIDD) trial randomly assigned 384 patients

with hypertension and diastolic dysfunction (but no HF)

to aggressive antihypertensive therapy with valsartan or

placebo-based therapy [34]. While there was no benefit

to valsartan compared to other antihypertensives, blood

pressure reductionper sewas associated with an improve-

ment in diastolic LV relaxation, as estimated by tissue

Doppler echocardiography. However, none of these stud-

ies were performed in patients with a clinical diagnosis of

HFpEF.Aronow and Kronzon first showed in a small, open

label study of patients with HFpEF and prior MI that

enalapril improved functional class and exercise time

while reducing LV mass [85]. The first large scale ran-

domized study in HFpEF was the Candesartan in Heart

Failure-Assessment of Reduction in Mortality (CHARM)-

Preserved trial, comparing the ARB candesartan with

placebo [3]. After a median follow-up 36 months, treat-

ment with candesartan was associated with a nonsignif-

icant reduction in the composite endpoint in mortality

and cardiovascular hospitalizations, but the primary end-

point was not met [3]. More recently, the I-PRESERVE

(Irbesartan in Heart Failure with Preserved Systolic Func-

tion) trial assigned 4128 patients with HF and an EF

greater than 45% to irbesartan or placebo [5]. After

4 years of follow-up there was again no difference in

death or cardiovascular hospitalizations. These trials em-

phasize the disconnect in HFpEF literature between in-

termediate endpoints such as hypertrophy regression or

exercise capacity (both improved with ARBs [83,84]) and

clinical events.

The Perindopril in Elderly People with Chronic Heart

Failure (PEP-CHF) trial enrolled 850 patients aged

70 years to perindopril or placebo and found that

perindopril was associated with a trend toward decreased

all-cause mortality and hospitalization for heart failure at

1 year, but over the entire 3 year study period there was

no reduction in the primary endpoint [4]. However, therewas substantial cross over between treatment groups dur-

ing the study, and event rates were lower than antici-

pated. In contrast to CHARM and I-PRESERVE, signifi-

cant improvements in symptoms (New York Heart Asso-

ciation (NYHA) class) and functional status (6 min walk)

were seen in the perindopril arm, though secondary anal-

yses must be viewed with caution in light of the negative

primary endpoint [3,5].

Beta Blockers

By slowing heart rate, -adrenergic antagonists may al-

low for a longer diastolic filling period. While this is

clearly useful with tachycardia or in patients with mi-

tral stenosis, the utility of beta blockers in patients with

normal resting heart rates is unclear, because slowing

the heart rate in this range tends to simply prolong di-

astasis, where transmitral flow is absent [86]. Because

chronotropic incompetence is common in HFpEF and is

intimately linked to reduced exercise capacity [15,41],

beta-blockade may in fact worsen symptoms of exertional

intolerance. Unfortunately prospective trial data regard-

ing beta blockers in HFpEF is lacking.

The Swedish Doppler-echocardiographic (SWEDIC)

trial randomized 113 patients with HFpEF (EF > 45%)to carvedilol or placebo. After 6 months there was no im-

provement in a composite echo-Doppler diastolic func-

tion score [87]. A prospective observational study by

Dobre et al. showed that in HF patients with EF > 40%,

survival was increased in those prescribed -blockers

[88], but another recent observational study from Farasat

et al. found that beta blocker use may be associated

with increased risk for cardiovascular hospitalization in

women with HFpEF [89]. Retrospective analysis from the

large Organized Program to initiate Lifesaving Treatment

in Hospitalized Patients with Heart Failure (OPTIMIZE-

HF) registry showed that beta blocker use in HFpEF was

not associated with improved survival or a reduction in

hospitalizations, in striking contrast to observed findings

in HFrEFagain raising questions regarding the utility of

beta blockers in HFpEF [90].

An early open-label randomized trial in patients with

previous myocardial infarction, heart failure and an EF >

40% showed that propranolol compared to no propra-

nolol improved mortality and increased ejection frac-

tion after 1 year [91]. However, this population with



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prior Q-wave infarction and somewhat depressed LVEF

might have been expected to benefit more from beta-

blockade than HFpEF patients without coronary disease

or as much systolic dysfunction (i.e., EF 4049%). The

more recent Study of the Effects of Nebivolol Interven-

tion on Outcomes and Rehospitalization in Seniors with

Heart Failure (SENIORS) Trial, which enrolled patientsaged 70 years with both reduced and preserved EF,

demonstrated the benefit of nebivolol versus placebo in

the primary outcome of mortality and cardiovascular hos-

pitalization [92]. One subsequent analysis from SENIORS

suggested the benefits were restricted to those with re-

duced EF [93], whereas a more recent subanalysis indi-

cated that the benefit was present regardless of EF [94].

Nebivolol is highly -1 specific and has additional nitric

oxide-dependent vasodilating properties, so these results

may not apply to other -blockers. Importantly, no trial

specifically enrolling nonischemic HFpEF with higher EF

(>50%) has been published to date, and there is concern

that many patients with mildly depressed EF (4049%)

may more closely resemble HFrEF than HFpEF. Prospec-

tive trial data on the effectiveness of beta-blockers in HF-

pEF patients that are representative of those seen in the

community are urgently needed.

Diuretics

As in HFrEF, diuretics play a key role in controlling symp-

toms of volume overload in HFpEF. By reducing central

congestion, the ventricle may operate in a more compli-

ant portion of its pressurevolume relationship [95]. Di-

uretics are less useful in patients without clinical evidenceof volume overload, and because of enhanced preload-

sensitivity in HFpEF, their use may be hazardous in euv-

olemic patients [39]. There is little data regarding diuretic

use in HFpEF. In a retrospective analysis of the ALLHAT

Trial, the thiazide diuretic chlorthalidone decreased the

incidence of HFpEF in hypertensive patients compared to

lisinopril, amlodipine, and doxazosin [96]. In the Hong

Kong Diastolic Heart Failure Study, patients with HFpEF

were randomized to diuretics alone or diuretics plus irbe-

sartan or ramipril [97]. Quality of life scores improved in

all groups, leading the authors to conclude that diuret-

ics improve symptoms in HFpEF, but absent a placebo

control, it cannot be determined how much of the symp-

tomatic improvement was ascribable to diuretic therapy.

Nitrates

Direct nitric oxide (NO) donors such as nitrates in-

crease cellular levels of cyclic guanosine monophosphate

(cGMP), a key second messenger that activates kinases

that may improve diastolic relaxation and compliance

[98]. Nitrates also decrease preload, allowing the ventri-

cle to function at lower volumes, where operating stiff-

ness may be lower [25,99]. Despite a multitude of the-

oretical mechanisms of benefit to enhancing NO signal-

ing in HFpEF, there is little clinical data. McCallister et al.

showed that administration of nitroglycerin can mitigate

the acute increase in LV filling pressures during supineexercise in patients with coronary disease and normal

controls [100]. Use of short or long acting nitrates may

prove useful to treat symptoms of dyspnea in patients

with HFpEF, particularly when patients are euvolemic

and diuretics are not indicated. Novel therapies that en-

hance cGMP signaling appear promising and represent an

area of active investigation [101].

Calcium Channel Blockers

Setaro et al. showed in a study of 20 patients with HF-

pEF that treatment with verapamil compared to placebo

resulted in significantly reduced symptoms, increasedLV diastolic filling rates and increased mean exercise

time [102]. This was corroborated by Hung et al. in

similar echo-Doppler study [103]. Verapamil may also

reduce ventricular-arterial stiffening and improve exer-

cise capacity in healthy older-aged patients [104]. By

regressing hypertrophy and controlling blood pressure,

dihydropyridine calcium channel blockers may prevent

or deter the development of HFpEF [83,96]. However,

as with -blockers, diuretics and nitrates, large scale

randomized trial data using calcium antagonists are not

available.

Aldosterone Antagonists

Aldosterone promotes cardiac hypertrophy and fibro-

sis [105], and its inhibition might be expected to re-

duce the ventricular-vascular stiffening and diastolic dys-

function characteristic of HFpEF. In a small randomized

study, Mottram et al. showed an improvement in sev-

eral echocardiographic measures of myocardial function

in patients with hypertensive heart disease, normal EF

and exertional dyspnea with spironolactone [106]. The

large, NIH-sponsored TOPCAT trial comparing spirono-

lactone to placebo in HFpEF is currently enrolling patients

and should help resolve this question.

Digitalis

While digoxin is often considered for its inotropic

actions in HFrEF, it also displays favorable effects

on baroreceptor function and reductions in sympa-

thetic activation and neurohormonal stimulation, sug-

gesting a potential role in HFpEF [107]. In an ancil-

lary analysis of 988 patients with HFpEF (EF > 45%)



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enrolled in the Digitalis Investigations Group (DIG) trial,

Ahmed et al. found that digoxin had no effect on heart

failure mortality or hospitalization [108]. At the protocol-

specified 2 year follow up there was a reduction in HF

death or hospitalization (driven by the latter), but over

the median 37 month follow up, this difference was not

present. Of note, the majority of HFpEF patients in theDIG trial had HF related to an ischemic etiology (56%),

and there was an unanticipated increase in hospitaliza-

tions for unstable angina in the digoxin group which

largely offset the nonsignificant reduction in HF hospi-

talization [108]. Ischemic disease is not the predominant

cause of HFpEF in population-based studies [1,2,26], and

as such, these results may not be applicable to many HF-

pEF patients encountered in the community.

Statins

In a prospective observational study of 137 HFpEF pa-

tients treated at the discretion of their primary physi-

cians, Fukuta et al. found that after a mean follow-up

of 21 months, statin therapy was associated with signif-

icantly lower mortality (relative risk 0.20), whereas An-

giotensin Converting Inhibitors (ACEI), ARB, -blockers,

and calcium channel blocker therapy had no association

with survival [109]. However, the GISSI-HF (Effect of ro-

suvastatin in patients with chronic heart failure) Trial,

which tested the effects of rosuvastatin on death and

death or cardiovascular hospitalization in patients with

chronic HF, found no benefit in the subgroup of patients

included with preserved EF (>40%; n = 465) [110].

Nonmedical Treatments

Revascularization

Myocardial ischemia acutely causes both systolic and

diastolic dysfunction [111], and may contribute to ab-

normal cardiovascular reserve with stress [15,112], sug-

gesting that revascularization may be beneficial in pa-

tients with HFpEF. However, retrospective data suggests

that episodes of acute pulmonary edema tend to reoc-

cur despite coronary revascularization in this population

[113], and while prospective data is lacking in HFpEF, the

recently presented heart failure revasculartization trial

(HEART) Trial observed no benefit to revascularization in

patients with HFrEF (EF 35%) and viable myocardium

[114]. HEART was underpowered due to low enrollment

(n = 69 randomized,n = 45 revascularized), and the un-

reported STITCH trial [115] may shed more light on the

role of revascularization in HF. Similar to HEART, this

trial included only patients with LV systolic dysfunction

(EF 35%). Until prospective data is available in HFpEF,

the role of coronary revascularization will remain unclear

and must be considered on a case-by-case basis.

Renal artery stenosis may cause paroxysmal hyperten-

sion and pulmonary edema, producing a form of sec-

ondary HFpEF. Renal revascularization percutaneously

or surgically in such patients can be extremely effec-

tive, and evaluation for renal artery stenosis is warrantedin patients with recalcitrant hypertension and episodes

of acute pulmonary edema, particularly if there is evi-

dence of atherosclerosis elsewhere [116]. Enthusiasm has

been tempered with the recent publication of the Angio-

plasty and STent for Renal Artery Lesions (ASTRAL) Trial,

which found no benefit to renal revascularization regard-

ing renal function or blood pressure control in patients

with renal artery stenosis [117]. However, this was not a

study of HF patients, who would be expected to be more

vulnerable to the effects of uncontrolled hypertension.

Indeed, it is established that renal revascularization effec-

tively treats recurrent pulmonary edema in appropriately

selected HF patients with renal artery stenosis [118].

Exercise

Exercise capacity is reduced in HFpEF to a similar magni-

tude as seen in HFrEF [119]. Exercise programs improve

aerobic capacity and functional status in HFrEF [120] and

may potentially improve other abnormalities in HFpEF

such as endothelial dysfunction [50]. There is little pub-

lished data regarding the role of exercise training in HF-

pEF, though two trials are currently examining this im-

portant question [121,122]. Cross-sectional data suggests

that conditioned athletes have better diastolic ventricularcompliance than apparently healthy sedentary patients

[123,124] and animal data from Brenner et al. suggest di-

rect benefit of exercise training in the aging heart [125].

In contrast to possible beneficial effects on ventricular

compliance, Prasad et al. found in a cross sectional study

that prior endurance training among older subjects was

not associated with abrogation of age-associated deterio-

ration in diastolic relaxation [126]. Longitudinal data are

lacking, and short-term interventional trials have demon-

strated variable effects of exercise training upon diastolic

function [127].

Others

Diastolic stiffening of the ventricle in HFpEF increases re-

liance on the atrial contribution to filling. Accordingly,

loss of the latter with atrial fibrillation, which is com-

mon in HFpEF [26], can lead to clinical decompensation.

While trials of rate versus rhythm control have not been

performed in HFpEF, it is recommended that restoration

and maintenance of sinus rhythm be strongly considered



9/17


in patients with HFpEF and atrial fibrillation [95]. Sleep

disordered breathing is common in all patients with HF,

and because obesity is a common risk factor for HFpEF,

sleep apnea should be evaluated for and treated in appro-

priate patients. As in HFrEF, anemia is common in HFpEF

[69], and trials of erythropoietin analogues are currently

enrolling [128].

Emerging Therapies and FutureDirections

With the failure of conventional HFrEF therapies noted

in published trials, current investigations are focusing

on novel therapeutic targets in HFpEF. Because of their

pleiotropic actions on multiple underlying mechanisms,

there is enthusiasm that phosphodiesterase-5 inhibitors

(PDE5I) may be efficacious in HFpEF. PDE5I attenuate

adrenergic stimulation [129], reduce ventricular-vascular

stiffening [130] and LV remodeling [131], improve en-

dothelial function [132], and reduce pulmonary vascu-

lar resistance [133]. There is also evidence that they

may enhance renal responsiveness to endogenous natri-

uretic peptides [134]. The PDE5I sildenafil is currently

being tested in the ongoing RELAX (Evaluating the Ef-

fectiveness of Sildenafil at Improving Health Outcomes

and Exercise Ability in People With Diastolic Heart Fail-

ure) Trial [62], which will evaluate the effects of PDE5I

on exercise capacity, functional status and ventricular

form and function. Because aldosterone similarly dis-

plays adverse pleiotropic effects promoting ventricular

hypertrophy, fibrosis, vascular stiffening and endothelialdysfunction [135], there is also hope that aldosterone

antagonists will be of benefit in HFpEF. The large

TOPCAT (Aldosterone Antagonist Therapy for Adults

with Heart Failure and Preserved Systolic Function)

trial, which will determine the role of spironolactone in

HFpEF, and is actively enrolling [136]. Finally, an-

other class of agents that modulates both ventricular

and vascular function, the Rho-kinase inhibitors, also

may represent a potential novel therapeutic approach in

HFpEF. Rho-kinase inhibitors such as fasudil and Y-

27632 have demonstrated the ability to blunt progression

of cardiomyocyte hypertrophy and cardiac remodeling in

animal models of heart failure [137].

Modulation of heart rate is another area of active study.

Given the recent documentation of chronotropic incom-

petence in HFpEF [15,24,40,41], rate adaptive atrial pac-

ing is currently being evaluated in the Restoration of

Chronotropic Competence in Heart Failure Patients With

Normal Ejection Fraction (RESET) trial, which will ex-

amine the effects of pacing on exercise capacity in pa-

tients with HFpEF [138]. In contrast, another trial is test-

ing whether heart rate reduction using the If channel

blocker ivabradine may be of benefit [139]. Because au-

tonomic dysfunction appears to play a role in HFpEF [15],

it has been postulated that direct carotid sinus stimulation

might improve symptoms in patients with HF via reduc-

tion in heart rate, improvements in baroreflex sensitiv-

ity, changes in nitric oxide bioavailability, antiarrhythmiceffects, or central modulation [140]. Currently there is

no data regarding effects of parasympathetic activation in

HFpEF.

Changes in myocyte stiffness and extracellular ma-

trix are strongly implicated in the pathogenesis of ab-

normal chamber compliance in HFpEF [141]. This may

be due to both quantitative and qualitative changes in

collagen. Glucose crosslinking (glycation) increases with

aging and decreases tissue compliance, suggesting that

this may be a therapeutic target. Alagebrium chloride

(ALT-711) is a novel compound that breaks glucose

crosslinks and improves ventricular and arterial compli-

ance in animals [142] and reduces blood pressure and

vascular stiffness in human hypertension [143]. ALT-711

was studied in an open label fashion in 23 patients with

HFpEF and shown to lead to reduction in left ventricular

mass and improvements in diastolic filling and quality of

life [144]. A placebo controlled, randomized trial of ALT-

711 was implemented but has since been terminated.

Transforming growth factor-beta (TGF-) is emerging as

an important pro-fibrotic hormone in cardiovascular dis-

eases, and infusion of TGF- neutralizing antibody in a

rat model of pressure overload was associated with re-

duction in fibrosis and prevention of diastolic dysfunction

[145]. Matrix metalloproteinases play a role in modulat-ing ventricular stiffening with hypertensive heart disease,

and therapies targeting these pathways may prove effec-

tive for HFpEF [146]. The cellular macromolecule titin

has emerged as a major determinant of resting myocyte

tension [147]. Titin is expressed as two isoforms in hu-

mans, the stiffer N2B and the more compliant N2BA, and

alteration of these expression patterns could be exploited

therapeutically. Recent studies have further shown that

titin has phosphorylation sites that dynamically regulate

its resting tension, and these represent exciting new tar-

gets for drug development [147149].

Because both systolic and diastolic ventricular reserve

responses with exercise are impaired in HFpEF, it seems

plausible that there might be a problem with myocyte en-

ergy utilization or availability [6,15,24]. Smith et al. first

showed abnormal ATP phosphocreatine shuttle kinetics

in HFpEF [46], and these results has more recently been

confirmed by Phan et al. [24]. As such, novel therapies

targeting myocardial energy substrate utilization may be

useful in HFpEF and are currently under investigation

[150].



10/17


Oxidative stress in common in HFrEF and promotes

ventricular and endothelial dysfunction. Xanthine oxi-

dase inhibitors such as allopurinol have been shown to

reduce oxidative stress and improve myocardial contrac-

tile reserve acutely in HFrEF [151], though a subsequent

clinical trial did not show a benefit [152]. Oxidative stress

promotes uncoupling of nitric oxide synthase (NOS), andthe consequent loss of downstream effectors (cGMP) may

exacerbate diastolic dysfunction, promote maladaptive

remodeling, and produce endothelial dysfunction. Treat-

ment with tetrahydrobiopterin (BH4), an essential cofac-

tor of endothelial NOS, has recently been shown in ani-

mal models of pressure overload to attenuate remodeling

and improve NOS coupling [153]. Treatments designed

to re-couple NOS and/or improve cGMP signaling may

eventually prove useful in HFpEF [101,154].

The anti-anginal drug ranolazine has been postu-

lated as a potential treatment for HFpEF, as it blocks

inward sodium current and thereby reduces myocyte

calcium levels, possibly enhancing relaxation and/or

diastolic stiffness, as suggested in animal studies [155].

However, this treatment remains to be tested in human

HFpEF. Finally, mechanical devices designed to improve

early diastolic relaxation and enhance ventricular suc-

tion are currently being developed and studied in ani-

mal models, though data is very preliminary. These de-

vices work by storing energy expended during systolic

contraction to enhance recoil and suction during early

diastole.

ConclusionsHFpEF remains a major public health problem, but un-

fortunately there is little evidence guiding how best to

treat it. In the absence of trial data documenting bene-

fit, current guidelines simply emphasize control of blood

pressure and volume overload [27]. Importantly, careful

follow up is paramount in HFpEF, particularly among the

elderly, because commonly used medications such as va-

sodilators and diuretics may produce exaggerated drops

in blood pressure because of ventricular-arterial stiffen-

ing, while beta blockers or nondihydropyridine calcium

antagonists may exacerbate pre-existing chronotropic in-

competence. Recent work has emphasized the impor-

tance of noncardiac comorbidities in HFpEF, and in the

absence of therapies of proven efficacy, it is essential to

treat these accordingly. Important steps have been made

in our mechanistic understanding of HFpEF over the past

10 years, and these and further advances will hopefully

allow for the design of better and more specific treat-

ments for this ever-expanding half of the heart failure

population.

Conflict of Interest

There are no conflicts of interest or financial disclosures.

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