JACC: CARDIOVASCULAR IMAGING VOL. -, NO.

-, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART PAPER

Asymptomatic Left Ventricular

Diastolic Dysfunction
Predicting Progression to Symptomatic Heart Failure

Wojciech Kosmala, MD, PHD,a,b,c Thomas H. Marwick, MBBS, PHD, MPHb,c

ABSTRACT

Asymptomatic left ventricular diastolic dysfunction (ALVDD) (diastolic abnormalities and normal ejection fraction in
the absence of symptoms) is associated with incident heart failure (HF) and decreased survival. Abnormalities of
diastolic function might therefore be included in the definition of stage B HF, which denotes individuals at risk for the
development of HF. Imaging techniques, especially echocardiography, are necessary for the recognition of preclinical
left ventricular (LV) diastolic disturbances, as well as further tracking of pathological changes and responses to
treatment. The transition of ALVDD to symptomatic HF is underlain by multiple factors, including both cardiovascular
and noncardiovascular determinants. The initiation of management strategies targeting cardiovascular and systemic
comorbidities in patients identified as having ALVDD may delay symptomatic progression and improve prognosis.
(J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.

H eart failure (HF) remains a growing medical

and economic problem, associated with
high morbidity and mortality rates. By
2030, its prevalence in the United States is expected
symptomatic cardiac impairment is a priority in car-
diovascular medicine. Imaging techniques, especially
echocardiography, are necessary for the recognition
of preclinical myocardial disturbances, as well as
to increase by 25% to 30%, with a concomitant >2- further tracking of pathological changes and re-
fold increase in the cost of HF care (1). The occurrence sponses to treatment.
of overt HF is preceded by a phase of clinically silent
disease. Asymptomatic left ventricular diastolic ALVDD AND STAGE B HF
dysfunction (ALVDD) is defined by the presence of
diastolic abnormalities and normal ejection fraction Asymptomatic left ventricular (LV) impairment is the
(EF) in the absence of HF symptoms (2). ALVDD can defining feature of stage B heart failure (SBHF)—a
evolve to symptomatic HF, contributing to the overall category characterized by a high risk of subsequent
HF burden. Both the development and further pro- progression to the clinical HF syndrome (3). The
gression of ALVDD are stimulated by comorbidities, current definition of SBHF is based on the presence of
especially hypertension, diabetes, obesity, coronary decreased LVEF, abnormal regional myocardial
artery disease, and atrial fibrillation. Given the contractility, LV enlargement, hypertrophy, or
limited potential for improvement in advanced HF, valvular disease, and reflects a previous era of
preventive measures impeding the development of focusing on ischemic HF with reduced EF.

From the aCardiology Department, Wroclaw Medical University, Wroclaw, Poland; bMenzies Institute for Medical Research,
University of Tasmania, Hobart, Australia; and the cBaker Heart and Diabetes Institute, Melbourne, Australia. Dr. Kosmala has
reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Marwick has received research
grant support from GE Medical Systems. Sherif Nagueh, MD, served as the Guest Editor for this paper.

Manuscript received August 16, 2018; revised manuscript received October 1, 2018, accepted October 1, 2018.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2018.10.039

2 Kosmala and Marwick
Progression of Asymptomatic Diastolic Dysfunction
ABBREVIATIONS Conversely, the exclusive reliance on the
AND ACRONYMS previous criteria may not be sufficient to
ascertain SBHF underlain by nonischemic
ALVDD = asymptomatic left
ventricular diastolic
etiologies, such as hypertension, diabetes,
dysfunction and obesity, in which a large proportion of
ASE = American Society of cases are featured by preserved EF. A broader
Echocardiography definition for SBHF incorporating LV dia-
EACVI = European Association stolic dysfunction and impaired global lon-
of Cardiovascular Imaging
gitudinal strain (GLS) may be useful for
EF = ejection fraction
contemporary practice (4–8). The inclusion of
GLS = global longitudinal these new elements in the SBHF definition is
strain
justified by their influence on exercise ca-
HF = heart failure
pacity. This appears to be highly important in
HFpEF = heart failure with
view of the significance of exercise intoler-
preserved ejection fraction
ance as a fundamental criterion for the
RAAS = renin-angiotensin-
aldosterone system
recognition of overt HF.
The extended SBHF definition is consis-
SAHF = stage A heart failure
tent with the concept of early myocardial
SBHF = stage B heart failure
disease presented in the 2016 American
Society of Echocardiography (ASE)/European Asso-
ciation of Cardiovascular Imaging (EACVI) recom-
mendations on diastolic function (9). As both LV
diastolic and longitudinal systolic disturbances may
stem from a common pathological background,
they may develop in parallel. Thus, the presence
of impaired GLS or other indices of longitudinal
contractility reinforces the finding of diastolic
dysfunction, since all these aberrations are mani-
festations of myocardial impairment—although they
do not always occur together. Similarities in the
clinical impact between LV diastolic and longitudinal
systolic abnormalities might be underpinned by the
fact that they both contribute to the decline in
exercise capacity (10) that can precede the develop-
ment of overt HF.
The prevalence of ALVDD in the general population
assessed before the introduction of the new 2016 ASE/
EACVI recommendations ranged between 25% and
35%, with mild ALVDD accounting for 70% to 80%
(11,12). However, this estimate is affected by some
interstudy differences in the criteria used to define
this condition. The development of ALVDD is pro-
moted by increasing age and comorbidities, and in the
high-risk elderly population, the frequency of ALVDD
has been shown to be 47.6% for mild ALVDD and
16.5% for moderate-to-severe ALVDD (11). Further-
more, the majority of subjects (86%) with at least
moderate LV diastolic dysfunction and preserved EF
remain in the preclinical stage according to the Fra-
mingham HF criteria (12).
The application of the 2016 ASE/EACVI scoring
system resulted in a substantially lower prevalence of
ALVDD, which in population-based cohorts was only
1.3% to 1.4% (13,14). However, the major limitation of
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
- 2019:-–-
the previously cited studies is that neither of them
considered the presence of myocardial disease,
identified on the basis of additional findings, which is
an integral part of the updated diagnostic strategy.
Moreover, the use of retrospectively acquired data-
sets might have contributed to the missing of diag-
nostically relevant information, thus increasing the
proportion of subjects with an indeterminate diastolic
status. A recently demonstrated greater specificity of
the new approach for the recognition of heart failure
with preserved ejection fraction (HFpEF) (15) is
consistent with the prognostic superiority of this
strategy over previous diagnostic algorithms (16).
Nonetheless, the preference of specificity versus
sensitivity may differ in the application of the algo-
rithm to diagnose ALVDD rather than HFpEF. Further
prospective studies are warranted to ascertain the
discriminatory capacity of the 2016 recommendations
to identify ALVDD.
ASSESSMENT OF
LV DIASTOLIC DYSFUNCTION
RESTING PARAMETERS. According to recent guide-
lines (9), the algorithms for diagnosing and grading
diastolic dysfunction are based on an integrated
assessment of mitral inflow, annular velocities, left
atrial volume, and tricuspid regurgitant velocity.
Although other echocardiographic parameters are
supposed to play only an auxiliary role, novel
markers such as diastolic strain and strain rate,
untwisting rate, as well as right ventricular quanti-
tation and atrial strain may provide additional infor-
mation (Figure 1).
An important diagnostic advance may be the
introduction of tissue characterization using cardiac
magnetic resonance T1-mapping imaging, which has
been demonstrated to facilitate delineation of the
symptomatic phase of HFpEF (17). Extracellular vol-
ume quantitated by this technique reflecting inter-
stitial fibrosis represents a morphological substrate
for increased LV stiffness and diastolic dysfunction.
In the cross-sectional analysis, extracellular volume
progressively deteriorated across the HF stages and
was associated with reduced exercise capacity. It
should be however emphasized that for the time be-
ing, T1-mapping is primarily a research tool. The
wider use of this modality is constrained by cost,
availability, and the lack of an appropriate thera-
peutic strategy.
EXERCISE RESPONSE. The recognition of diastolic
dysfunction without evidence of elevated LV filling
pressure at rest is insufficient to explain exertional
dyspnea. Another important diagnostic pitfall is the
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Kosmala and Marwick 3
- 2019:-–- Progression of Asymptomatic Diastolic Dysfunction

F I G U R E 1 New Diastolic Parameters That Might Be Useful in Providing More Sensitive or Specific Evidence of
Left Ventricular Diastolic Dysfunction

A B
Peak systolic Strain at 1/3
strain diastole

Untwisting rate

(A) Diastolic strain (%) ¼ (peak  1/3 diastole) / peak. (B) Left ventricular untwisting rate. (C) Strain rate during isovolumic relaxation (SRIVR)
and early diastole (SRe). AVC ¼ aortic valve closure; AVO ¼ aortic valve opening; MVO ¼ mitral valve opening.

adequacy of categorization of symptoms. Some pa-
tients without obvious symptoms due to sedentary
lifestyle or manifesting symptoms attributed to other
factors such as obesity can be misclassified as
asymptomatic or symptomatic, respectively. In such
cases, the definition of LV functional reserve at ex-
ercise testing is of particular value. Measurement of
diastolic and other cardiovascular variables during
exercise may better correspond with the actual
functional status than the characteristics obtained at
rest. In addition to the evaluation of LV diastolic
response to exertion (as determined by E/e 0 ratio and
tricuspid regurgitant velocity) (Figure 2), this
approach can provide relevant information on other
determinants of functional capacity, specifically sys-
tolic and chronotropic reserve, myocardial ischemia,
or exaggerated blood pressure increase (18–21).
Accordingly, exercise echocardiography including LV
4 Kosmala and Marwick JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Progression of Asymptomatic Diastolic Dysfunction - 2019:-–-

F I G U R E 2 Exercise Echocardiography Suggesting Left Ventricular Filling Pressure Elevation

E Septal e’ TRV

E/e’
Rest
12.3

E/e’
Peak
16.3

Worsening of exercise tolerance may be associated with an abnormal left ventricular diastolic response to exertion (E/e0 ratio 16.3, tricuspid regurgitant velocity [TRV]
3.08 m/s).

filling pressure estimation might be useful for diag-
nosing HF, especially HFpEF (18). Normal reference
values for diastolic stress testing are presented in
Table 1. The assessment of LV deformation response
to exercise may further address the question of
imminent clinical deterioration; however,
approach needs the determination of normative
ranges. The appearance of pulmonary congestion
resulting from LV filling pressure elevation might be
confirmed during stress testing by lung ultrasound
detection of B-lines, as has been demonstrated for
patients with reduced EF (22).
SINGLE CUTPOINT VERSUS AGE- AND SEX-SPECIFIC
REFERENCE LIMITS FOR DIASTOLIC DYSFUNCTION.
Both age and sex influence myocardial diastolic
properties. Normal aging itself is associated with
some alterations in the heart muscle, including
decreased relaxation and compliance. Sex-related
variations in hormonal status, circulating natriuretic
peptides, and ventricular-arterial coupling (23,24)
may account for the differences in LV diastolic met-
rics between men and women, and adjustment of
diastolic indices for age and, to a lesser degree, for
sex affects cardiovascular risk stratification (25,26).
Using age- and sex-specific criteria, LV diastolic
dysfunction is identified in 25% and 30% of in-
dividuals across age groups, and both mild and
moderate-to-severe diastolic impairments
associated with increased clinical risk. On the other
hand, with single cutpoint (age- and sex-
independent) criteria, diastolic dysfunction is un-
common in persons younger than 50 years of age,
whereas in the elderly it was identifiable in the ma-
this jority of population. When the latter method of
assessment was used, only moderate-to-severe dia-
stolic dysfunction was predictive of incident cardio-
vascular disease (26).
The implementation of age-appropriate reference
limits to define diastolic abnormalities revisits the
relationships between myocardial impairment and
underlying contributors. The potential benefit of this
approach is that LV diastolic dysfunction recognized
in that way is more closely attributable to modifiable
risk factors than age, which seems important in the
context of preventive interventions.
The assessment of LV diastolic function can be also
confounded by high heart rates. Specifically,
tachycardia-induced fusion of early and late diastolic
Doppler signals of mitral inflow and annular veloc-
ities may pose a diagnostic problem.
PROGRESSION TO SYMPTOMATIC HF
SYMPTOMS AND FUNCTIONAL CAPACITY. In gen-
eral, exercise capacity in SBHF is lower than in stage
A heart failure (SAHF) (4,5,17,18). However, symp-
were toms are unreliable and special attention may need to
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Kosmala and Marwick 5
- 2019:-–- Progression of Asymptomatic Diastolic Dysfunction

be paid to patients with impaired exercise capacity

T A B L E 1 Normal Reference Values of Doppler Parameters Assessed During Treadmill and
despite their asymptomatic status. The defining Bicycle Diastolic Stress Testing
feature for this subset should be peak oxygen con-
Treadmill (74) Bicycle (75)
sumption or 6-min walk test distance sizably reduced
Rest Exercise Rest Exercise
below the reference limits (<80% predicted). This
E, cm/s 73  19 90  25 73  17 96  19
subcategory in HF staging requires a more detailed
A, cm/s 69  17 87  22 62  13 90  22
characterization; however, as the further clinical
DT, ms 192  40 176  42 201  15 185  20
course and prognosis in these patients might be less e0 septal, cm/s 12  4 15  5 10  3 13  3
favorable, closer surveillance should be considered. e0 lateral, cm/s — — 14  4 17  4
PROGRESSION TO OVERT HF. In its natural history, E/e0 septal 6.7  2.2 6.6  2.5 7.3  1.5 7.4  1.4
ALVDD may deteriorate and progress to heart failure E/e0 lateral — — 5.6  1.4 5.8  1.2

with preserved ejection fraction (HFpEF) or even to E/e0 average — — 6.3  1.4 6.4  1.2

HF with reduced EF. The prognostic significance of

Values are mean  SD.
this evolution extends further as evidenced by the A ¼ late diastolic mitral inflow velocity; DT ¼ deceleration time of E wave; e’ ¼ early diastolic mitral annular
association of worsening ALVDD with decreased sur- velocity; E ¼ early diastolic mitral inflow velocity.

vival. The rate of both progression to overt disease

(stage C) and associated mortality is determined by a
variety of factors, among which the profile of
comorbidities is of particular importance. A meta-
analysis of several studies including asymptomatic
patients with diastolic dysfunction revealed a 70%
increased risk of progressing to HF, which was lower
than that for asymptomatic LV systolic dysfunction.
The major predictors of transition to stage C included
age, diabetes, and elevated blood pressure and body
mass (27).
The population-based Olmsted County Heart
Function Study revealed that higher incidence of new
HF was associated with advancing age and a greater
prevalence of hypertension, diabetes, and coronary
artery disease; however, diastolic dysfunction was
predictive of the investigated outcome even after
adjustment for these factors (28). Serial assessments
of participants demonstrated that HF occurred at
follow-up in 2.6% of patients with normal diastolic
function, in 7.8% with mild diastolic dysfunction, and
12.2% with moderate-to-severe diastolic dysfunction,
regardless of the initial diastolic status at baseline
evaluation. This indicates the significance of the
temporal changes of ALVDD in the transition to a
clinically apparent disease. Another study based on
the Olmsted County population including individuals
with ALVDD and EF >50% showed that the 3-year
cumulative probability of development of stage C
was 11.6%, with a mortality of 10.1%. The advent of
HF was promoted by older age, renal dysfunction,
and higher right ventricular systolic pressure (29). In
a similarly selected cohort, the 2-year risk of devel-
opment of HF symptoms was 31%. This unfavorable
clinical course was independently associated with the
presence of hypertension and peripheral vascular
disease, which might imply that impaired ventricular-
arterial coupling may contribute to the progression of
ALVDD to overt disease (30).
Data from the Framingham Heart Study provided
evidence that in addition to established HF risk fac-
tors, the presence of noncardiac abnormalities such
as renal impairment, pulmonary limitation, or anemia
was each associated with a 30% increased risk of
incident HF (31). The association of superimposed
clinical events, such as poorly controlled blood pres-
sure, new onset atrial fibrillation, or infections with
incident HF, was revealed in a similar community-
based population with preserved EF (32).
The coexistence of ALVDD and diabetes, especially
with an inadequate metabolic control, may have a
particularly detrimental effect on prognosis. The 5-
year cumulative probability of incident HF was
36.9% in patients with diabetes and ALVDD compared
with 16.8% for individuals with normal diastolic
function, with death in 30.8% and 12.1%, respec-
tively. There was a 3% increase in the hazard of HF for
every 1-U increase in E/e 0 ratio (33). These data show
that the rates of incident HF and death in subjects
with diabetes and ALVDD are comparable to those in
the preclinical LV systolic dysfunction (34).
The predictive value of E/e 0 ratio in asymptomatic
diabetic and hypertensive heart disease was reported
in other studies (35–37). The independent prognostic
contribution from abnormal E/e 0 was not confirmed in
a recent paper including elderly persons with dia-
betes, among whom only left atrial volume and GLS
were independently predictive of the increased risk
of new HF or cardiovascular death (38).
The importance of the severity of LV diastolic
dysfunction in the evolution to symptomatic HF was
exhibited in the population with coronary artery
disease, normal EF, and no history of cardiac insuf-
ficiency. After adjustment for clinical factors, only
moderate-to-severe diastolic dysfunction was asso-
ciated with HF hospitalization and cardiovascular
death (39).
6 Kosmala and Marwick JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Progression of Asymptomatic Diastolic Dysfunction - 2019:-–-

T A B L E 2 Studies of the Association of LV Asymptomatic Diastolic Dysfunction With Incident HF and Other Adverse Outcomes

First Author, Age Reduced EF Follow-Up

Year (Ref. #) Study Population (yrs) (%) (yrs) Incident HF (Annual %) Death (Annual %) Modeling

Kane et al., General 61 2.4 6.3 Normal diastolic function

2011 (28) 0.4%
Mild LV diastolic
dysfunction 1.2%
Moderate-to-severe LV
diastolic dysfunction
1.9%
Correa de Sa Moderate-to-severe 63 0 2 Any HF symptom 15.5%
et al., 2010 LV diastolic Framingham criteria 1%.
(30) dysfunction
Vogel et al., Moderate-to-severe 67 0 3 Symptomatic HF 3.9% Death 3.4%
2012 (29) LV diastolic
dysfunction
From et al., Diabetes mellitus 60 Mean EF 5 LV diastolic dysfunction LV diastolic
2010 (33) 62  9% 7.4% dysfunction 6.2%
No LV diastolic No LV diastolic
dysfunction 3.4% dysfunction 2.4%
Ren et al., LV diastolic dysfunction 67 0 3 LV diastolic dysfunction Only moderate-to-severe
2007 (39) and ischemic heart 2.8% LV diastolic dysfunction
disease independently
associated with adverse
outcome
Lam et al., General 76 5 11 LV diastolic dysfunction Noncardiac risk factors
2011 (31) 2.2% (renal, pulmonary,
hematologic): each
associated with 30%
higher risk of
symptomatic HF
Yang et al., Elderly with HF risk 70 0 1.2 HF or CV death 10.3%
2016 (40) factors
(hypertension,
diabetes, obesity)
Shah et al., General (elderly) 75.3 3 1.7 HF or death: Incident HF or death with
2017 (25) SBHF 2.8%; reclassified morphofunctional
SAHF 1.6%; abnormalities:
nonreclassified SAHF 2 abnormalities: HR 2.34
1.4% (95% CI: 1.49–3.67);
3 abnormalities: HR 6.30
(95% CI: 3.83–10.35)

CI ¼ confidence interval; CV ¼ cardiovascular; EF ¼ ejection fraction; HF ¼ heart failure; HR ¼ hazard ratio; LV ¼ left ventricular; SAHF ¼ stage A heart failure; SBHF ¼ stage B heart failure.

The practical applicability of echocardiography in with incident HF and other adverse outcomes is pre-
risk stratification in the preclinical disease was sented in Table 2.
demonstrated in the TASELF (TAsmanian Study of
Echocardiographic detection of Left ventricular DETERMINANTS OF PROGRESSION TO
dysfunction) study encompassing a community- SYMPTOMATIC HF
based elderly population with HF risk factors (hy-
pertension, diabetes, obesity) and normal EF. Among The complexity of the progression from an asymp-
the independent predictors of new HF in this cohort tomatic phase to symptomatic HF stems from a het-
were left atrial enlargement, LV hypertrophy, erogeneous influence of multiple clinical and
abnormal GLS, and E/e 0 . A diagnostic algorithm pathophysiological domains. Cardiovascular risk fac-
allowing for identification of the low-, intermediate-, tors, such as advanced age, hypertension, diabetes,
and high-risk subsets was based on left atrial volume obesity, coronary artery disease, or peripheral
index (cutpoint 34 ml/m 2), GLS (cutpoint 18%), and E/ vascular disease, contribute to the development of
e 0 ratio (cutpoint 13) (40). The presence of 2 parame- ALVDD, as well as to overt HF. Noncardiac comor-
ters reflecting diastolic performance in the prognos- bidities, especially renal, pulmonary, and hemato-
tication process underscores the contribution of logic (anemia) disturbances, may accelerate the
diastolic abnormalities to the development of clini- development of HF symptoms. The involvement of
cally overt HF. A summary of studies assessing the extracardiovascular components supports the
association of LV asymptomatic diastolic dysfunction concept of HF as a systemic condition and might
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Kosmala and Marwick 7
- 2019:-–- Progression of Asymptomatic Diastolic Dysfunction

C ENTR AL I LL U STRA T I O N Factors Determining the Disease Progression Across Asymptomatic and Symptomatic
HF Stages

CV risk factors
(age, CAD, hypertension, Non-cardiac risk factors
diabetes, obesity, atrial (renal, pulmonary,
fibrillation, peripheral hematologic)
vascular disease)

Stage A HF Stage B HF Symptomatic HF

CV reserve Peripheral
(systolic, diastolic, mechanisms
ventricular-arterial (impaired O2 extraction
coupling, chronotropic) and utilization)

Kosmala, W. et al. J Am Coll Cardiol Img. 2019;-(-):-–-.

Cardiovascular (CV) risk factors contribute to the transition from both stage A heart failure to stage B heart failure and from stage B heart failure to symptomatic
disease. The development of clinically overt heart failure (HF) is also determined by noncardiac risk factors, reduced CV reserve, and, probably, impaired peripheral
mechanisms. CAD ¼ coronary artery disease.

provide explanation for a relatively large proportion infiltration, abnormal neurohormonal activity,
of noncardiac deaths in this entity (41). advanced glycation end-products, decreased nitric
The transition of ALVDD to symptomatic (stage C) oxide availability, and an increase in proin-
HF is related to the onset of hemodynamic de- flammatory mediators (2,27). Diastolic dysfunction
rangements. The rate of these alterations is however cannot be considered as a precursor to symptomatic
unknown and may differ depending on the clinical HF in isolation from other pathological components;
circumstances. In brief, abnormal LV distensibility— LV contractile derangements and myocardial struc-
an inherent component of diastolic dysfunction— tural alterations (e.g., LV hypertrophy and remodel-
leads to the impairment in LV inflow, with a pro- ing) have synergistic roles to ALVDD. Each of these
gressive dependence on filling at atrial contraction. features is associated with gradual progression from
This finally results in the elevation of left atrial stage A through stage B to symptomatic HF
pressure to maintain LV filling and cardiac output. (4,5,17,18), and they contribute incrementally to ex-
The increase in LV filling pressure and pulmonary ercise intolerance. However, it remains unclear
capillary wedge pressure occurs initially during whether the association with exercise capacity or
exertion, thus triggering pulmonary congestion and symptoms of exercise intolerance is linear or
exercise intolerance. Over time, other HF symptoms nonlinear. The latter might be supported by the fact
may appear, accounting for the clinical presentation that the prevalence of symptomatic disease increases
in individual patients. after reaching established thresholds by LV filling
The specific pathophysiological and molecular pressure estimates (e.g., E/e 0 ).
factors governing the transition from ALVDD to overt An extremely important contribution to the pro-
HF are poorly understood; however, it can be gression to symptomatic phase of HF arises from the
postulated that the likely contributors include reduction of cardiovascular functional reserve
changes in collagen deposition and titin, myocardial resulting from the underlying disease-associated
8 Kosmala and Marwick JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
Progression of Asymptomatic Diastolic Dysfunction - 2019:-–-

Analogous to the progression of symptomatic HF

F I G U R E 3 Proportion of Subjects With Features of Stage B Heart Failure in
Each Risk Group
severity (18), it is likely that the development of
stage C HF is linked with the abnormalities in mul-
Prevalence of Stage B Heart Failure tiple domains. In an elderly asymptomatic cohort
50% from the ARIC (Atherosclerosis Risk In Communities)
49%
study, both LV diastolic dysfunction and impaired
GLS provided independent and incremental infor-
40%
40% mation to conventional echocardiographic measures
34%
associated with HF hospitalization or death. Howev-
30% 31%
32%
31% er, on an individual basis, increased risk for a detri-
mental course was demonstrated only for patients
20% 22% with at least 2 of the 3 LV diastolic, systolic, and
20%
structural aberrations (25). Similar results were ob-
14% tained in the TASELF study, in which a statistical
10% 12%
9% 9%
significance of the increased rate of adverse events
was shown only for the combination of impaired
0% diastolic function and GLS, but not for isolated dia-
ABNORMAL LV LA ABNORMAL
E/e’ HYPERTROPHY ENLARGEMENT GLS stolic or systolic disturbances (44). These data
convincingly suggest the existence of a cumulative
Low Risk High Risk Entire Cohort
effect of LV diastolic and systolic derangements on
the occurrence of overt HF; however, additional in-
Abnormal E/e0 , global longitudinal strain (GLS), and left ventricular (LV) hypertrophy
vestigations dedicated to this issue are needed.
were more marked in patients at higher risk, but this relationship was not apparent for
left atrial (LA) volume (34).
Likewise, abnormalities of arterial tree may syner-
gize with ALVDD in the transition to stage C (45–47).
Increased arterial stiffness, associated with similar risk
factors to myocardial impairment, promotes ALVDD by
deterioration of myocardial and vascular properties. stimulating LV hypertrophy and reducing coronary
Impaired responses to exercise may precede func- perfusion (45), and should be considered as a relevant
tional derangements occurring at rest, as has been component of HF pathophysiological framework and
evidenced for LV filling estimates (E/e 0 ) and LV potential target for interventions.
deformation (18), and have a crucial detrimental Even in the absence of any symptomatic manifes-
impact on exertional capacity. Finally, disturbed pe- tations, silent myocardial ischemia may contribute to
ripheral mechanisms of oxygen extraction and utili- the development of preclinical and clinically
zation in the skeletal muscles should be considered as apparent disease, especially in patients with diabetes.
potential determinants of the development of overt Accordingly, such a scenario should not be ignored
HF. However, the role of this pathophysiological when planning diagnostic strategies in at-risk
factor in the transition phase between asymptomatic patients.
and symptomatic disease needs to be validated. The A question remains open about the reversibility of
contributors to the disease progression across HF progression to symptomatic HF. This aspect was to
stages are shown in the Central Illustration. some extent addressed in the analysis of the NIL-
From a clinical point of view, it is critical to CHF (Nurse-led Intervention for Less Chronic Heart
identify asymptomatic individuals who are at Failure) study participants (5). A favorable trajectory
heightened risk of developing symptoms. The of exercise capacity was observed in patients with
different manifestations of subclinical dysfunction the improvement in elevated E/e0 ratio over time.
do not necessarily coincide, and they are differen- The only echocardiographic parameters which
tially represented in patients at different levels of correlated with improvement in 6-min walk test
risk (Figure 3) (42). Moreover, they may have distance at a 3-month follow-up were diastolic
different implications for outcome (Figure 4) (43). indices: e0 and E/e 0 . These findings are consistent
The presence of different combinations of the with the cross-sectional evidence of increased E/e 0
aforementioned determinants, as well as various corresponding to a reduction in exercise tolerance,
degrees of the severity of underlying pathologies and provide a rationale that exercise capacity may be
may be among the reasons that not all patients with responsive to interventions successfully targeting LV
the same extent of diastolic dysfunction progress. function (4,48–50).
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019 Kosmala and Marwick 9
- 2019:-–- Progression of Asymptomatic Diastolic Dysfunction

F I G U R E 4 Clustering of Pathophysiologic Features in Stage B Heart Failure Associated With Diabetes Mellitus, and Their Association
With Outcome

e’ lateral

e’ septal -Strain

E/A ratio

LVMi E/e’ ratio

LVEDVi -LVEF LA area

LA volume
LVESVi

B
30
Patients with Event (%)

20

10

Log-rank p-value = 0.049

0

0 1 2 3 4 5 6 7 8
Time Since Enrollment (Years)
Number at Risk (Events)
Cluster 1 214 (1) 200 (1) 180 (1) 156 (1) 125 (3) 102 (1) 79 (2) 45 (0) 16
Cluster 2 168 (1) 165 (2) 162 (4) 155 (5) 140 (5) 161 (5) 112 (5) 84 (0) 42
Cluster 3 139 (0) 133 (3) 125 (1) 114 (3) 95 (1) 84 (5) 54 (2) 35 (1) 6

(A) Visualization of clustering. (B) Event-free survival across the clusters. Cluster 1 (green) is characterized by men with relatively preserved
systolic and diastolic function, who have a follow-up event rate of about 1% per year. In contrast, cluster 2 (blue, comprising obese and
hypertensive women with diastolic dysfunction) and cluster 3 (orange, men with left ventricular [LV] hypertrophy and systolic dysfunction)
have an annualized event rate of about 2.5% (43) (LA ¼ left atrial; LVEDVi ¼ left ventricular end-diastolic volume index; LVEF ¼ left
ventricular ejection fraction; LVMi ¼ left ventricular mass index; LVESVi ¼ left ventricular end-systolic volume index.

SCREENING STRATEGIES: based mainly on LVEF and LV structural criteria

ECHOCARDIOGRAPHY AND BEYOND (4,5,17,44). The implementation of diastolic indices
and GLS into the echocardiographic screening proto-
Accumulating data support the need of extending col seems to be a reasonable step, providing an in-
SBHF definition beyond the traditional approach cremental value in the identification of individuals
10 Kosmala and Marwick
Progression of Asymptomatic Diastolic Dysfunction
F I G U R E 5 Incident Heart Failure in Different Etiologies of SAHF
Survival Functions T2DM-SAHF vs Other-SAHF
1.0
Other-SAHF
Cumulative Event-Free Survival
0.8
T2DM-SAHF
0.6
0.4
0.2
Log-rank test χ2 = 5.36
0.0 p = 0.021
6 12 18 24 30
Months
Patients with diabetes are more likely than other stage A heart failure (SAHF) patients to
progress to overt heart failure (51). T2DM ¼ type 2 diabetes mellitus.
prone to develop incident HF (44), especially those
with diabetes mellitus (51) (Figure 5). The information
obtained from LV diastolic and longitudinal defor-
mation parameters covers a wider pathophysiologic
area and pertains to earlier phases of the natural
history of cardiac impairment, thus allowing for a
more effective HF risk prediction. This is particularly
important for nonischemic HF etiologies, in which an
EF-based definition of SBHF may leave some at-risk
cases undetected (38).
ROLE OF NATRIURETIC PEPTIDES. The accuracy of
natriuretic peptides as biomarkers in the preclinical
disease has been reported to be diminished because
of a lesser degree of stress put on the myocardium as
compared with the symptomatic stage (52). In the
subgroup of the Cardiovascular Health Study patients
with preserved EF, the addition of N-terminal pro–B-
type natriuretic peptide to echocardiographic pa-
rameters including fractional shortening, left atrial
size, LV mass and E/A ratio slightly improved net
reclassification index across HF risk categories (53). In
an “at-risk” population, B-type natriuretic peptide–
based screening followed by echocardiography and
collaborative health care were associated with the
reduction of the combined rates of LV dysfunction
and HF (54). The potential diagnostic significance of
natriuretic peptides in early HF stages may be sup-
ported by the fact that the subset of participants of
the ARIC study reclassified from stage A to B on the
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
- 2019:-–-
basis of diastolic parameters and GLS was character-
ized by higher N-terminal pro–B-type natriuretic
peptide than the nonreclassified stage A subjects (25).
The combined use of natriuretic peptides and echo-
cardiography may be more effective in asymptomatic
individuals with an intermediate-to-high risk of overt
HF predicted on the basis of clinical data (53).
OTHER BIOMARKERS. The use of other blood bio-
markers is less well evidenced. High levels of sero-
logical markers of collagen turnover—collagen type I
carboxy-terminal telopeptide and procollagen type
III N-terminal propeptide in subjects free of overt
cardiovascular disease have been shown to be asso-
ciated with incident HF, especially with preserved EF
(55–57). Galectin-3, a marker of fibrosis, proved to be
predictive of abnormal diastolic response to exercise
in HFpEF patients (58); however, its diagnostic use-
fulness in the preclinical stages of HF requires further
investigations.
CLINICAL IMPLICATIONS
The management approaches in SAHF and SBHF pa-
tients are not identical. The focus of preventive
strategies in SAHF is the control of HF risk factors,
whereas the aim of cardioprotective therapies in
SBHF is the delay and reduction of HF burden
resulting from cardiovascular impairment. The
pivotal issue determining a different sort of approach
in SBHF is the fact that adverse events, including the
progression to the symptomatic HF, occur is this
subset more often and earlier than in SAHF. However,
the clinical data on the efficacy of treatment strate-
gies in ALVDD are scarce. Most of the previous evi-
dence on SBHF management comes from the
populations with an EF-based systolic dysfunction
(59–66). The results of these studies support the use
of inhibitors of the renin-angiotensin-aldosterone
system (RAAS), as well as beta-blockers to improve
mortality, cardiovascular events, and development of
overt HF. A beneficial clinical effect of RAS inhibition
has been also observed in acute myocardial infarction
survivors without reduced EF and in patient cohorts
with a heightened cardiovascular risk (67–71). The
introduction of RAAS modifying treatments in high
risk participants of the STOP-HF (St. Vincent’s
Screening To Prevent Heart Failure) study was asso-
ciated with the retardation of progression to LV
dysfunction and the reduction of incident HF by 48%
(54).
Although the intention to treat analysis was nega-
tive in the TASELF study, analysis of those adherent
to therapy revealed a 77% decrease in hazard for the
composite of HF hospitalization or cardiovascular
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2019
- 2019:-–-
death in patients treated with RAAS inhibition and
beta-blockers on the basis of ALVDD and impaired
GLS (44). Although this secondary analysis demon-
strated clinical benefit from the redefinition of SBHF,
it should be treated with caution until it has been
corroborated by other investigations.
While medications with a direct myocardial effect
are preferred, some data suggest that ALVDD may
improve in response to blood pressure lowering, irre-
spective of the class of drugs used in therapy (72).
In addition to medical treatment, some non-
pharmacological interventions, such
training, appropriate diet, alcohol and smoking
cessation, and vaccinations may also be useful in the
prevention of symptomatic HF development (73) and
should be considered as adjunct therapies.
CONCLUSIONS
ALVDD is an integral component of preclinical cardiac
impairment. Therefore, there is a clear need to
include diastolic abnormalities in the definition of
SBHF to facilitate the identification of individuals
who are at increased risk of progression to symp-
tomatic HF and other adverse cardiovascular events.
Although the mechanisms responsible for the transi-
tion to clinically overt disease are still insufficiently
understood, the current evidence indicates that pre-
emptive management strategies targeting cardiovas-
cular and systemic comorbidities may represent a
reasonable approach to delay symptomatic progres-
sion and improve prognosis. As the efficacy of these
interventions should be assessed in relation to their
cardioprotective effects, echocardiographic surveil-
lance may aid to achieve the desired clinical benefits.
In the context of the worsening HF epidemic, further
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KEY WORDS global longitudinal strain,
heart failure with preserved ejection fraction,
left ventricular diastolic dysfunction, stage B
heart failure