REVIEW

CURRENT
OPINION Diastolic heart failure: diagnosis and therapy
Alina Nicoara and Mandisa Jones-Haywood

Purpose of review
This article focuses on the recent findings in the diagnosis and treatment of diastolic heart failure (DHF) or
heart failure with preserved ejection fraction.
Recent findings
DHF has become the most common form of heart failure in the population. Although diastolic dysfunction
still plays a central role, it is now understood that DHF is a very complex clinical entity with heterogeneous
Downloaded from http://journals.lww.com/co-anesthesiology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 11/15/2020

pathophysiology and significant contribution from extracardiac comorbidities. Alterations in ventricular-

arterial coupling play a significant role in the impaired hemodynamic response to exercise seen in these
patients. The absence of diastolic dysfunction at rest does not exclude the diagnosis of DHF. There has
been little to no progress made in identifying evidence-based, effective, and specific treatments for patients
with DHF. This may be because of the pathophysiological heterogeneity, incomplete understanding of DHF,
and heterogeneity of patients included in clinical trials with variable inclusion criteria.
Summary
The understanding of the phenotypic heterogeneity and multifactorial pathophysiology of DHF may lead to
novel therapeutic targets in the future. Currently, the key to the treatment of DHF is aggressive management
of contributing factors.
Keywords
diagnosis, diastolic function, heart failure preserved ejection fraction, therapy

INTRODUCTION fraction seems to be favored in the existing litera-

Heart failure is a diagnosis associated with consider- ture, for the purpose of this review, we will use the
able morbidity and mortality. More than 5 million term DHF.
people in the USA carry this diagnosis with a sober-
ing mortality rate of 50% at 5 years from diagnosis
PATHOPHYSIOLOGY
[1]. Although heart failure with reduced ejection
fraction is a well understood, well studied entity Despite its importance, our understanding of the
in cardiovascular medicine, heart failure with pre- pathophysiology of DHF is still incomplete.
served ejection fraction has only recently been Traditionally, it was assumed that the only pathol-
identified as a clinical entity. It is considered to ogy responsible for this disorder is impaired filling
account for at least 50% of all heart failure cases and diastolic dysfunction, hence the label of DHF. It
and be responsible for the majority of heart failure is now understood that diastolic dysfunction plays
hospital admissions. Its incidence will only increase a central role, but is not the solitary contributor
in the coming years as the population ages [2]. Heart to the diagnosis of DHF. Additional contributing
failure with preserved ejection fraction is defined by pathophysiologic mechanisms include: abnormal
the American College of Cardiology and American
Heart Association as the presence of clinical symp-
toms or signs of heart failure in a patient with a left Division of Cardiothoracic Anesthesiology and Critical Care Medicine,
Department of Anesthesiology, Duke University Medical Center, Durham,
ventricular ejection fraction (LVEF) greater than
North Carolina, USA
50% with evidence of diastolic dysfunction by Dop-
Correspondence to Alina Nicoara, MD, FASE, Division of Cardiothoracic
pler echocardiography or cardiac catheterization [3]. Anesthesiology and Critical Care Medicine, Department of Anesthesi-
Several labels have been used to describe the same ology, Duke University Medical Center, Box 3094/5691F HAFS, Erwin
clinical entity such as heart failure with preserved Rd Durham, NC 27710, USA. Tel: +1 919 681 0862; fax: +1 919 681
ejection fraction, heart failure with normal ejection 8994; e-mail: [email protected]
fraction, and diastolic heart failure (DHF). Although Curr Opin Anesthesiol 2016, 29:61–67
the term heart failure with preserved ejection DOI:10.1097/ACO.0000000000000276

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diagnostic techniques of myocardial deformation,

KEY POINTS several studies have shown subtle changes in sys-
 DHF is considered to account for at least 50% of all tolic function including reduced longitudinal
heart failure cases and be responsible for the majority strain, impaired systolic twist, torsional dyssyn-
of heart failure hospital admissions. Its incidence will chrony, and reduced myocardial systolic reserve
only increase in the coming years as the [11]. Also, there is recent evidence that there is slow
population ages. but progressive decline in ejection fraction in
 The presence of normal LV geometry and normal patients with DHF; therefore, these patients will
diastolic function at rest does not exclude the diagnosis eventually be diagnosed with heart failure with
of DHF. reduced ejection fraction [12,13]. Dunlay et al.
showed that in patients with DHF, on an average,
 There has been little to no progress made in identifying
ejection fraction decreased by 5.8% over 5 years with
evidence-based, effective, and specific treatments for
patients with DHF. Currently, the key to the treatment of greater declines in older individuals and in those
DHF is aggressive management of contributing factors with coronary artery disease. Overall, 39% of the
such as hypertension and atrial fibrillation. patients initially diagnosed with DHF had a
LVEF < 50% at some point after the diagnosis [12].
Recently, a third population of heart failure patients
has been described, heart failure with recovered
ventricular-arterial coupling, systolic dysfunction, ejection fraction [14]. These patients have a distinct
pulmonary hypertension, neuroendocrine dysfunc- clinical phenotype, biology, and prognosis and may
tion, chronotropic incompetence, inflammation, be misclassified as DHF. Although systolic function
and multiple comorbidities such as obesity, hyper- is seemingly normal or near-normal at rest, patients
tension, and atrial fibrillation. Understanding of with DHF demonstrate a blunted hemodynamic
some of these complex mechanisms may offer response to exercise through the inability to
opportunities for developing diagnostic and thera- increase accordingly LVEF, stroke volume, and car-
peutic strategies [4]. diac output. Factors that are thought to contribute
to this phenomenon include low stroke volumes
because of a concentrically remodeled small LV
Diastolic dysfunction cavity, b adrenergic receptor desensitization, chro-
Increased left ventricle (LV) stiffness produces resist- notropic incompetence, mechanical dyssynchrony,
ance to LV filling and it is a common finding in and abnormal myocardial deformation.
patients with DHF. Increased LV stiffness is linked to
sarcomere structural alterations because of post-
translational modifications of titin, a sarcomere Abnormal ventricular-arterial coupling
&&
protein responsible for myocardial stiffness [5 ,6]. Ventricular-vascular coupling is defined as the ratio
Although increased myocardial stiffness may be of arterial to ventricular elastance and reflects the
present in the absence of LV hypertrophy and fib- interaction of the heart with the systemic vascula-
rosis, the presence of the aforementioned changes in ture. Increased arterial stiffness and an inadequate
the thickened myocardium further accentuates the response to exercise through an inability to vaso-
increase in LV stiffness. Impaired LV relaxation is a dilate can be seen in patients with DHF [15,16]. The
universal finding in patients with DHF as a result of attenuated reduction in mean vascular resistance
disturbances in adenosine triphosphate or calcium together with the previously described limited sys-
levels [7]. This phenomenon is independent of the tolic reserve lead to dynamic limitations in ventric-
presence of structural abnormalities such as LV ular-arterial coupling with exercise seen in patients
&&
hypertrophy or increased LV stiffness [5 ]. Several &&
with DHF [17 ].
mechanisms responsible for impaired relaxation
have been described including bioavailability of
nitric oxide and proinflammatory cytokines [8,9]. Right ventricle-pulmonary vascular unit
dysfunction
Traditionally, chronic pulmonary venous hyperten-
Systolic dysfunction sion and the resultant increase in right ventricle
Different cut-offs for the key criterion of DHF have (RV) afterload have been considered the main causes
been used during the past years across classifi- of RV dysfunction in patients with DHF. In a recent
cations, trials, and registries ranging for LVEF > 40% community-based study, 64% of patients with DHF
&&
40% to a LVEF > 50% [10 ], with the current defi- had a pulmonary artery systolic pressure greater
nition using the 50% cut-off. However, using newer than 40 mmHg. In the same study, 35% of patients

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 Diastolic heart failure: diagnosis and therapy Nicoara and Jones-Haywood

had some degree of RV dysfunction by tricuspid enrolled in the Treatment of Preserved Cardiac
annulus systolic plane excursion. Compared with Function Heart Failure with an Aldosterone
patients with normal RV function, patients with any Antagonist (TOPCAT) trial before initiation of
RV dysfunction (mild and moderate to severe com- randomized therapy found that 14% had normal
bined) were more likely to have atrial fibrillation, LV geometry, 34% concentric remodeling, 43% con-
permanent pacing, and treatment with diuretics centric hypertrophy, and 9% eccentric hypertrophy
[18]. RV dysfunction was associated with clinical [20]. The echocardiographic substudy of the Irbe-
and echocardiographic evidence of more advanced sartan for Heart Failure with Preserved Ejection
heart failure and with poorer outcome [18]. More Fraction (I-PRESERVE) trial found that 46% of the
recently, it has been recognized that some patients patients enrolled had normal LV geometry [21].
develop RV dysfunction out of proportion to the These findings also have prognostic significance.
degree of pulmonary hypertension and additional The I-PRESERVE trial found LV mass and LV hyper-
etiological factors may be involved [19] such as atrial trophy to be predictive of morbidity and mortality
fibrillation, moderate to severe tricuspid regurgita- in patients with DHF [21]. The newer modalities of
tion, and RV pacing. analyzing myocardial mechanics have challenged
the concept of normal LV systolic function in
patients with DHF. In a study assessing LV systolic
DIAGNOSIS function by speckle tracking analysis, Kraigher-
The diagnosis of DHF is based on the presence of Krainer et al. found that compared with both normal
heart failure symptoms, absence of LV systolic dys- controls and hypertensive heart disease patients,
function, and the exclusion of other cardiac or non- patients with DHF demonstrated significantly lower
cardiac conditions which may be the cause of the longitudinal and circumferential strain. Reduced
clinical presentation. History and physical examin- strain was associated with acute hospitalization
ation are instrumental in determining the presence and higher N-terminal pro-BNP levels [22]. In a
of symptoms and signs of heart failure. However, the similar fashion, mechanical dyssynchrony was
clinical presentation is similar in both systolic heart assessed in patients with DHF enrolled in the Pro-
failure (SHF) and DHF, and therefore it is not helpful spective comparison of ARNI with ARB on Manage-
in discriminating the type of heart failure. The ment Of heart failUre with preserved ejectioN
electrocardiogram may reveal LV hypertrophy and fraction Trial (PARAMOUNT). The investigators
left atrial enlargement in patients with DHF, but the found that patients with DHF had greater LV dys-
absence of these findings does not exclude the diag- synchrony compared with healthy controls and that
nosis. Chest radiography can exclude other cardiac dyssynchrony was present even in patients with
or pulmonary pathology responsible for the present- LVEF  55% and narrow QRS. Worse LV dyssyn-
ing signs and symptoms. Brain natriuretic peptide chrony was associated with a wider QRS interval,
(BNP) and pro-BNP levels tend to be lower in lower mitral annular relaxation velocity, and higher
patients with DHF when compared with patients LV mass [23].
&&
with SHF and may be within normal limits [5 ]. An
algorithm of the diagnosis of DHF is presented in
Fig. 1. Left ventricle diastolic function
Echocardiography is a versatile tool in the diag- Assessment of diastolic function plays a key role in
nosis of DHF, and it is recommended as the primary the diagnosis of DHF. Several review articles describe
noninvasive test in patients with new onset heart the echocardiographic modalities used to evaluate
failure. Echocardiography is unique in its ability to diastolic function, and it is not in the scope of this
provide information on LV systolic and diastolic study to detail technical aspects of each technique
function, volumes, RV function, hemodynamics, [24]. One of the challenges in evaluating diastolic
and valvular lesions. function is that patients with DHF are most often
asymptomatic at rest but symptomatic with exer-
cise, and therefore in some patients the indices of
Left ventricle structure and systolic function diastolic function may be within normal limits at
Patients with DHF have a high prevalence of struc- rest. Several clinical trials have found that up to one-
tural heart disease such as concentric LV remodeling third of the patients enrolled had normal patterns of
and concentric hypertrophy. However, the presence diastolic function as assessed at rest (TOPCAT –
of normal LV geometry does not exclude the diag- 34%, I-PRESERVE – 31%, PARAMOUNT – 8%)
nosis of DHF. Existing data from several clinical [20,21,23]. These findings emphasize the fact that
trials show significant heterogeneity in patients normal diastolic function at rest does not exclude
with DHF. Echocardiograms obtained in patients the diagnosis of DHF. In selected patients, diastolic

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Signs or symptoms of heart failure

EF> 50%
NT-proBNP≤ 220 pg/ml or BNP≤ 200 pg/ml Extra-cardiac cause
and pulmonary disease or anemia
or deconditioning or other extra-cardiac disease

EF< 50%
Systolic heart failure
NT-proBNP> 220 pg/ml or BNP> 200 pg/ml

EF> 50% and LVEDVI < 97 ml/m2

Invasive hemodynamics: Tissue doppler Tissue doppler Biomarkers:

mPCWP> 12 mmHg E/E’ > 15 15> E/E’> 8 NT- proBNP> 220 pg/ml
or LVEDP> 16 mmHg or BNP> 200 pg/ml
or tau> 48 ms
or B> 0.27

Exercise echocardiography
RVSP > 50 mmHg
If mPCWP< 18 mmHg and E/E’> 15
or
Exercuse invasive hemodynamic
Exercise invasive hemodynamic measurements
measurements mPCWP> 25 mmHg
mPCWP> 25 mmHg

Heart failure with preserved ejection fraction

FIGURE 1. Proposed diagnostic algorithm for diastolic heart failure. B, constant of left ventricular chamber stiffness; BNP, B-
type natriuretic peptide; E’, mitral annulus early diastolic velocity as evaluated by tissue Doppler; E, transmitral early diastolic
velocity; EF, ejection fraction; LVEDP, left ventricular end-diastolic pressure; LVEDVI, left ventricular end-diastolic volume index;
mPCWP, mean pulmonary capillary wedge pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; RVSP, right
ventricle systolic pressure. This figure is adapted with permission from [30] and from Wachter R, Edelman F. Diagnosis of
heart failure with preserved ejection fraction. Heart Failure Clinics 2014; 10:399-406.

dysfunction can be unmasked by acquisition of for patients with DHF [27]. Among the many ques-
echocardiographic data during or after provocative tions still unanswered regarding DHF is whether
&& &&
tests (exercise or dobutamine) [5 ,25 ]. Exercise the current existing stages of diastolic function
stress echocardiography and cardiopulmonary exer- are optimal for clinical use, since some patients
cise testing appear to be useful tests in this dynamic are difficult to categorize using the recommended
&&
assessment of DHF. In a recent study, 87 patients algorithm for grading diastolic function [25 ]. A
with hypertension, exertional dyspnea, and normal large observational study reported that patients fre-
resting LV systolic and diastolic function underwent quently (17% of patients examined at a clinical
exercise stress echocardiography and cardiopulmo- echocardiography laboratory) had intermediate
nary exercise testing. Increase of E/e0 > 15 occurred features between grades 1 and 2 (E/A ratio 0.75,
in 8/87 patients (9.2%) during maximal workload. deceleration time >140 ms, and E/e0 ratio 10) and
These patients had lower peak oxygen consumption had a worse prognosis than those with classic grade
(VO2), lower VO2 at anaerobic threshold, lower 1 dysfunction (differing in that E/e0 ratio 8) [28].
workload, lower peak partial pressure end tidal
carbon dioxide, and higher minute ventilation-
carbon dioxide production ratio (VE/VCO2) slope Left atrium size and function
[26]. Detailed guidelines regarding performance of Left atrial size and function assessment add incre-
cardiopulmonary exercise testing in patients with mental predictive information in the diagnosis of
heart failure have been described but are not specific patients with DHF. Left atrial enlargement is present

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 Diastolic heart failure: diagnosis and therapy Nicoara and Jones-Haywood

&&
in a majority of patients with DHF; 53% of patients extracardiac conditions [10 ]. Several drugs have
enrolled in the TOPCAT trial and 66% of patients been studied for the treatment of DHF: angiotensin
enrolled in the I-PRESERVE trial had some degree of II receptor blockers, angiotensin-converting enzyme
left atrial enlargement [20,21]. Recently, left atrial inhibitors, aldosterone antagonists, b-blockers,
reservoir, conduit, and pump function have been digoxin, and sildenafil (Fig. 2).
studied in a subset of patients enrolled in the PARA- Mineralocorticoid antagonists have been inves-
MOUNT trial using 2-dimensional volume indices tigated for the treatment of DHF based on the
and speckle tracking analysis and compared with participation of the renin–angiotensin–aldosterone
healthy controls of similar age and sex. Compared system in the pathogenesis of DHF. In the recent
with controls, DHF patients had worse left atrial TOPCAT trial, the effects of spironolactone have
reservoir, conduit, and pump function. Among been studied in patients with DHF. The primary
DHF patients, lower systolic left atrial strain was outcome was a composite of death from cardiovas-
associated with higher prevalence of prior heart cular causes, aborted cardiac arrest, or hospitaliz-
failure hospitalization and history of atrial fibrilla- ation for management of heart failure. The results
tion, as well as worse LV systolic function, higher LV showed that spironolactone did not reduce the inci-
mass, and left atrial volume [29]. dence of the primary composite endpoint [31]. It has
also been hypothesized that a reduction in heart rate
and therefore prolongation in diastolic filling time
THERAPY would result in more favorable LV filling and better
There has been little to no progress made in iden- coronary perfusion and would therefore mitigate
tifying evidence-based, effective, and specific treat- DHF symptoms. The effect of heart rate reduction
ments for patients with DHF. Drug classes, which on exercise capacity has been studied in patients
have been shown to improve outcomes in patients with DHF. Ivabradine, an If inhibitor of the sinoa-
with SHF, have proved ineffective in reducing trial pacemaker, devoid of effects on cardiac con-
mortality in DHF [30]. This may be because of the tractility has been compared with placebo in a
pathophysiological heterogeneity underlying DHF, recent randomized, crossover study. When com-
incomplete understanding of DHF, heterogeneity of pared with placebo, ivabradine significantly wors-
patients included in clinical trials with variable ened the change in peak VO2 in the DHF cohort and
inclusion criteria, or contribution to DHF by significantly reduced submaximal exercise capacity

Treat volume overload:

Diuretics
Mineralocorticoid antagonists-spironolactone
Avoid overdiuresis

Diet: Exercise training:

Low-salt Aerobic activity
Heart healthy More than 30 min x 3/week

Treat hypertension aggressively: Heart rate control*:

Diuretics Beta- blocking agents
ACE-Inhibitors Diltiazem and verapamil
Angiotensin receptor blockers Ivabradine
Hydralazine/isosorbide dinitrate

Additional treatment to consider:

Statins
Sildenafil (if pulmonary hypertension)
Weight loss treatment (if BMI> 30)

FIGURE 2. Therapeutic approach to diastolic heart failure. Heart rate control is paramount in patients with atrial fibrillation.
ACE, angiotensin converting enzyme. Adapted with permission from [5 ]. &&

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Table 1. Future therapies in diastolic heart failure

Therapy Hypothesized mechanism

Sildenafil Reduction in pulmonary pressure; reduction in cardiac fibrosis

Soluble guanylate cyclase antagonists Pulmonary and systemic vasodilation; inhibition of smooth muscle proliferation
Endothelin receptor antagonists Reduction in pulmonary pressure
Neprilysin inhibitors RAAS and inhibition of breakdown of natriuretic peptides
Ivabradine Increase time for diastolic filling
Iron supplements Antioxidant
Ranolazine Reduce intracellular calcium via reduction in late sodium current
Mitochondrial enhancement Restoration of ATP production and energy deficit
Serelaxin Pleiotropic effects
Statins Endothelial redox balance restoration; effects on collagen turnover
Isosorbide dinitrate and hydralazine Altered ventricular hemodynamics
Perhexiline Correct myocardial energy deficiency

RAAS, renin-angiotensin-aldosterone system. Adapted with permission from [30].

as determined by the oxygen uptake efficiency slope calcium handling has shown promising results in
[32]. Exercise training has been shown to improve patients with SHF [36] and may have a role in the
cardiorespiratory fitness in patients with SHF. In a future treatment of DHF.
recent meta-analysis of randomized clinical trials
that evaluated the efficacy of exercise training in Acknowledgements
patients with DHF, exercise training in patients with None.
DHF was associated with an improvement in cardi-
orespiratory fitness and quality of life even if there Financial support and sponsorship
were no significant changes in LV systolic or dias- Internal funding.
tolic function [33]. A prospective randomized, mul-
ticenter study is underway with the objective of Conflicts of interest
optimizing exercise training in prevention and
There are no conflicts of interest.
treatment of DHF study (OptimEx-CLIN) and defin-
ing the optimal dose of exercise training the DHF
[34]. A promising approach is targeting the treat- REFERENCES AND RECOMMENDED
&&
ment to a specific DHF phenotype [10 ]. In this READING
vein, serelaxin, a recombinant form of human Papers of particular interest, published within the annual period of review, have
been highlighted as:
relaxin-2, has been studied comparatively in & of special interest
patients with DHF and patients with SHF in the && of outstanding interest

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