European Heart Journal (2016) 37, 1807–1814 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehw120 Heart failure/cardiomyopathy

Risk factors for heart failure are associated

with alterations of the LV end-diastolic
pressure–volume relationship in non-heart
failure individuals: data from a large-scale,
population-based cohort
Michael Schwarzl 1,2*, Francisco Ojeda 1, Tanja Zeller 1,2, Moritz Seiffert 1,
Peter M. Becher1, Thomas Munzel3, Philipp S. Wild3, Maria Blettner4, Karl J. Lackner5,
Norbert Pfeiffer6, Manfred E. Beutel7, Stefan Blankenberg1,2, and Dirk Westermann1,2
1
Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; 2DZHK (German Centre for
Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg, Germany; 3Department of Medicine II, University Medical Center Mainz, Mainz, Germany; 4Institute for Medical
Biometrics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany; 5Institute of Clinical Chemistry and Laboratory Medicine, University Medical
Center Mainz, Mainz, Germany; 6Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany; and 7Department of Psychosomatic Medicine and Psychotherapy,
University Medical Center Mainz, Mainz, Germany

Received 16 October 2015; revised 12 January 2016; accepted 2 March 2016; online publish-ahead-of-print 7 April 2016

Aims Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure– volume relationship (EDPVR), which is dif-
ferent in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a
large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF
patients and their association to risk factors and all-cause mortality in non-HF individuals.
.....................................................................................................................................................................................
Methods Based on clinical and echocardiographic data, participants were divided into ‘No HF’ (n ¼ 14487), HFrEF (n ¼ 215), and
and results HFpEF (n ¼ 79). We estimated the position of the EDPVR and its stiffness-coefficient b from echocardiographic data
using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with ‘No HF’,
while the stiffness-coefficient b was increased in both HFrEF and HFpEF. In ‘No HF’, a higher stiffness-coefficient b was
associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated
with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were asso-
ciated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause
mortality.
.....................................................................................................................................................................................
Conclusion In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in
non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with
increased mortality.
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Keywords Heart failure † Pressure– volume relationship † Risk factor † Population-based study † Diastolic function

enlarged LV by definition, whereas in patients with HF and pre-

Introduction served ejection fraction (HFpEF) LV size is deemed to be normal
Changes in left-ventricular (LV) geometry and LV function are hall- compared with non-HF subjects. Impairment of systolic function is
marks in the development of chronic heart failure (HF). Patients suf- predominant in HFrEF, although diastolic function is frequently ab-
fering from HF with reduced ejection fraction (HFrEF) have an normal as well.1 Vice versa, diastolic dysfunction prevails in HFpEF,

* Corresponding author. Tel: +49 40 7410 18931, Fax: +49 40 7410 53622, Email: m.schwarzl@uke.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: journals.permissions@oup.com.

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 1808
but also systolic function is impaired in most patients as well.2 On
top of that, other non-cardiac comorbidities contribute to limited
exercise capacity, increased morbidity, and higher mortality in
both HFrEF and HFpEF.3
A cornerstone of diastolic dysfunction in HFpEF is a loss of LV
capacitance—i.e. a leftward shift of the LV end-diastolic pressure–
volume relationship (EDPVR)—next to increased LV stiffness
(Figure 1).2 In HFrEF, the LV EDPVR is shifted rightward.4,5
Both parameters of the LV EDPVR, LV capacitance and stiffness,
can be estimated by non-invasive, echocardiographic measures.6
This method can be applied to study cohorts in clinical trials but
also to large-scale, population-based studies and may increase our
knowledge on haemodynamic changes in HF and in the general popu-
lation. There are so far no data reported for the LV EDPVR in large
cohorts directly comparing HF patients to non-HF individuals.
Furthermore, while distinct risk factors are associated with HFrEF
or HFpEF, there is only little information about the association of
these risk factors with shape and position of the LV EDPVR, as well
as the clinical relevance of an altered LV EDPVR in non-HF individuals.
We thus investigated data from a large-scale, population-based co-
hort to (i) describe changes seen in HFpEF and HFrEF subgroups,
(ii) to associate risk factors for HFpEF or HFrEF with LV capacitance
and stiffness in non-HF individuals, and (iii) correlate LV capacitance
and stiffness with all-cause mortality in non-HF individuals.
Methods
Study population
The Gutenberg Health Study (GHS) is a large-scale, prospective,
population-based study investigating general and in particular cardiovas-
cular health in the city of Mainz and the district of Mainz-Bingen,
Germany. Between 2007 and 2012, a total of 15 010 participants
between 35 and 74 years of age underwent a standardized clinical as-
sessment including transthoracic echocardiography. The study was ap-
proved by the local Ethics Committee and it conforms with the
principles outlined in the Declaration of Helsinki. All participants gave
written informed consent to clinical examinations, to laboratory ana-
lyses, and to the use of data records for research purposes. Death
Figure 1 The left-ventricular (LV) end-diastolic pressure– volume relationship (LV EDPVR) can be characterized by the monoexponential fit
EDP ¼ a EDVb, in which EDP is LV end-diastolic pressure, EDV is LV end-diastolic volume, and a and b are curve-fit parameters. b is commonly
referred to as stiffness coefficient. (A) LV capacitance represents the LV end-diastolic volume at a given LV end-diastolic pressure, and is thus lower
in case of a leftward shifted LV EDPVR and higher in case of a rightward shifted LV EDPVR. (B) An increased stiffness-coefficient b, on the other
hand, results in a steeper LV EDPVR, while the LV EDPVR in total can be shifted left- or rightward.
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M. Schwarzl et al.
was ascertained by inquiring the official population register repeatedly.
A detailed description of the study design can be found elsewhere.7
Data analysis
Echocardiographic assessment included standard two-dimensional mea-
surements as well as continuous and pulse-wave Doppler measure-
ments (iE33 echocardiography system, S5 – 1 sector array transducer,
Royal Philips Electronics, Amsterdam, The Netherlands) and was per-
formed according to standard operating procedures by trained and cer-
tified medical technical assistants. Measurements were indexed to body
surface area (BSA) when appropriate. Left-ventricular ejection fraction
(EF) was calculated by biplane measurement according to Simpson.
The lateral mitral annular early diastolic velocity (e′ ) was determined
by spectral tissue Doppler imaging using standard methods. The ratio
of the early mitral inflow velocity (pulse-wave Doppler imaging) to e′
(E/e′ ) was determined in participants who presented in sinus rhythm
during echocardiography. N-terminal pro B-type natriuretic peptide
(NT-proBNP) values were available in the first 5000 participants only.
Records with missing data were excluded from analyses (n ¼ 205).
The remaining participants were divided into three groups: Participants
with either shortness of breath [according to New York Heart Associ-
ation (NYHA) functional class II – IV] or with medical treatment for HF
were classified as either ‘HFrEF’ (LV EF ,50%) or ‘HFpEF’ {LV EF ≥55%
and evidence of diastolic dysfunction: either (E/e′ ≥12) or [(8 ≤ E/e′ ,
12) and (E/A ≤0.5)]}.8,9 Participants fulfilling criteria for HFpEF but hav-
ing an LV EF between 50% and 55% (grey zone, n ¼ 24) were excluded
from analyses. All other participants were defined as ‘No HF’.
Obesity was defined as a body mass index of ≥30 kg/m2. Diabetes was
defined as either definite diagnosis by a physician, a fasting plasma glucose
level of ≥126 mg/dL or an incidental plasma glucose level ≥200 mg/dL.
Dyslipidaemia was defined as either a definite diagnosis by a physician
or by a low- to high-density-lipoprotein-ratio (LDL/HDL) of .3.5.
Hypertension was defined as either taking antihypertensive drugs, a
mean systolic blood pressure of ≥140 mmHg, or a mean diastolic blood
pressure of ≥90 mmHg (repeated measurements during 11 min of rest).
Non-invasive estimation of the left-ventricular
end-diastolic pressure– volume relationship
We used the method described by Klotz et al.6 to assess the LV EDPVR
non-invasively using the exponential curve-fit EDP ¼ a × EDVb, where
 LV EDPVR in a large-scale, population-based cohort 1809

EDP is the LV end-diastolic pressure, EDV is the LV end-diastolic vol-
ume, and a and b are curve-fit parameters. This method assumes a com-
mon underlying shape for volume-normalized EDPVRs and therefore
the curve-fit parameters a and b could be derived in each individual
participant from a single EDV/EDP data point. This method has been
applied in a population-based study before.10
EDV was measured by 2D-echocardiography (biplane measurement)
and EDP was derived using the equation EDP ¼ 11.96 + 0.596 × E/e′ .11
The curve-fit parameter b (i.e. stiffness coefficient) was used as a mea-
sure for LV end-diastolic stiffness. To compare the entire position of the
LV EDPVR, the calculated EDV at an EDP of 20 mmHg indexed to BSA
(EDVI20, i.e. LV capacitance) was used.10
Statistical analysis
Continuous variables were expressed as median and interquartile range
(25th and 75th percentile) and compared by the Mann – Whitney test
with Holm’s correction for multiple comparisons. Dichotomous vari-
ables were given in relative values and the x2 test with Holm’s correc-
tion was used. To account for effects of age and gender on LV EDPVR,
additional quantile (median) and logistic regression models, adjusted for
age and gender, were used with EDVI20 and the stiffness coefficient b as
the dependent variable. The Holm correction was used when present-
ing the P-values from these models.
To assess associations between risk factors and parameters of the LV
EDPVR in non-HF participants, multivariable linear regressions were
computed with EDVI20 or the stiffness coefficient b as dependent vari-
able, respectively, and risk factors as independent variables. Risk factors
included age, gender, obesity, diabetes, current smoker, dyslipidaemia,
hypertension, and estimated glomerular filtration rate (eGFR), the latter
estimated by the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation.12 Regression diagnostics for linear regressions
were examined. For these analyses, EDVI20 was log-transformed for
the residuals to better approximate normal distribution.
The association between the LV EDPVR and all-cause mortality in
non-HF participants was analysed using Cox regressions with EDVI20
or the stiffness coefficient b as independent variable. To allow for non-
linearities in the Cox regressions, cubic splines were used. The propor-
tional hazards assumption was assessed by tests and diagnostic plots
using the methods described by Grambsch and Therneau.13 Continuous
variables were log transformed as necessary. The models were adjusted
for age, gender, obesity, diabetes, current smoker, dyslipidaemia, hyper-
tension, and eGFR.
Results
Risk factors
Baseline characteristics of all participants are shown in Table 1. Both
HFrEF and HFpEF participants were older than ‘No HF’. The per-
centage of female participants was higher in the HFpEF subgroup

Table 1 Baseline characteristics

No HF (n 5 14487) HFpEF (n 5 215) HFrEF (n 5 79) P P P

No HF vs. No HF vs. HFpEF vs.
HFpEF HFrEF HFrEF
...............................................................................................................................................................................
Age (years) 55.0 (45.0– 64.0) 68.0 (63.0–72.0) 66.0 (56.3–70.0) ,0.001 ,0.001 0.016
Female gender (%) 49.4 65.1 27.6 ,0.001 ,0.001 ,0.001
Hypertension (%) 49.1 80.5 79.7 ,0.001 ,0.001 1.00
Diabetes (%) 6.9 33.5 27.8 ,0.001 ,0.001 0.44
Dyslipidaemia (%) 29.3 43.0 36.7 ,0.001 0.37 0.40
Obesity (%) 24.5 57.7 44.9 ,0.001 ,0.001 0.070
Current smoking (%) 19.4 14.4 21.5 0.23 0.75 0.40
Body mass index (kg/m2) 26.5 (23.9– 29.9) 31.3 (27.8–36.6) 29.6 (26.7–33.4) ,0.001 ,0.001 0.021
ACE-inhibitor/ARB (%) 22.7 54.9 64.4 ,0.001 ,0.001 0.18
Beta-blocker (%) 16.0 46.5 63.3 ,0.001 ,0.001 0.016
Aldosterone antagonist (%) 0.3 0.9 19.0 0.30 ,0.001 ,0.001
Loop diuretic (%) 1.8 16.7 40.5 ,0.001 ,0.001 ,0.001
Statin (%) 11.8 33.0 45.6 ,0.001 ,0.001 0.065
LAAI (cm2/m2) 8.1 (7.1–9.2) 8.7 (7.5–10.4) 9.7 (8.1– 12.1) ,0.001 ,0.001 ,0.001
RAAI (cm2/m2) 7.5 (6.6–8.5) 7.4 (6.6–8.6) 8.6 (7.4– 10.3) 0.63 ,0.001 ,0.001
IVSed (cm) 1.0 (0.9–1.1) 1.1 (1.0–1.2) 1.1 (1.0– 1.2) ,0.001 ,0.001 0.26
LVIDed (cm) 4.7 (4.4–5.1) 4.8 (4.5–5.2) 5.5 (5.0– 6.1) 0.37 ,0.001 ,0.001
LVPWed (cm) 0.9 (0.8–1.0) 1.0 (0.8–1.1) 1.0 (0.8– 1.1) ,0.001 ,0.001 0.13
LV EDVI (mL/m2) 51.8 (43.7– 60.9) 51.9 (42.8–62.7) 69.0 (52.3–84.0) 0.94 ,0.001 ,0.001
LV EF (%) 63.5 (60.0– 67.1) 64.6 (60.0–67.7) 44.9 (36.2–47.7) 0.043 ,0.001 ,0.001
E/e′ 7.1 (5.9–8.8) 13.8 (12.7–15.7) 9.3 (7.2– 12.8) ,0.001 ,0.001 ,0.001
NT-proBNP (pg/mL)a 60 (28–121) 138 (73–288) 956 (244– 1877) ,0.001 ,0.001 ,0.001

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LAAI, left-atrial area indexed to body surface are (BSA); RA, right-atrial area indexed to BSA; IVSed,
end-diastolic intraventricular septum width; LVIDedI, LV end-diastolic inner diameter indexed to BSA; LVPWed, LV end-diastolic posterior wall thickness; EDVI, LV end-diastolic
volume indexed to BSA; LV EF, LV ejection fraction.
a
Sample size for NT-proBNP was n ¼ 4815 in ‘No HF’, n ¼ 65 in HFpEF, and n ¼ 38 in HFrEF, respectively.

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 1810 M. Schwarzl et al.

and lower in HFrEF subgroup compared with ‘No HF’. The presence when compared with ‘No HF’ (4.2%, both P , 0.001, log-rank
of risk factors was more common in both HF entities compared with test). There was no significant difference between both HF sub-
‘No HF’. The average body mass index was higher in HFpEF than in groups (P ¼ 0.13).
HFrEF.

Echocardiographic data and N-terminal Left-ventricular end-diastolic

pro B-type natriuretic peptide
Echocardiographic parameters indicated dilative LV remodelling in
HFrEF and concentric LV remodelling in HFpEF (Table 1). Atrial dila-
tation, higher E/e′ , and elevated NT-proBNP levels were present in
both HF subgroups. As pre-defined, LV EF was preserved in HFpEF.
The median LV EF in HFrEF was 44.9%. A LV EF ,40% was present
in 27/79 (34.2%) participants in the HFrEF subgroup.
Survival
Kaplan – Meier estimates of eight-year all-cause mortality were in-
creased substantially both in HFpEF (34.6%) and HFrEF (35.0%)
pressure– volume relationship
In HFpEF, the LV EDPVR was shifted leftward (Figure 2A) corre-
sponding to a lower LV end-diastolic capacitance (i.e. the EDVI20,
Table 2 and Figure 2C). The stiffness coefficient was higher in HFpEF
compared with ‘No HF’ (Figure 2B). In HFrEF, the LV EDPVR was
shifted rightward and both LV end-diastolic capacitance and the stiff-
ness coefficient were higher than in ‘No HF’ (Figure 2A– C). After ad-
justing for age (quantile regression model) and gender (logistic
regression model), the leftward shift of the EDPVR in HFpEF was
no longer significant (P ¼ 0.85), while all other differences remained
significant.

Figure 2 (A) Mean left-ventricular end-diastolic pressure– volume relationships (LV EDPVR, solid lines) and 95% confidence intervals (dashed
lines). The LV EDPVR is significantly shifted leftward in HFpEF and significantly shifted rightward in HFrEF compared with non-HF individuals.
(B) LV stiffness coefficient b was higher in both HF subgroups compared with non-HF individuals, and higher in HFpEF than in HFrEF. (C ) LV cap-
acitance, that is, the LV end-diastolic volume at an end-diastolic pressure of 20 mmHg indexed to body surface area (EDVI20), was lower in HFpEF
and higher in HFrEF compared with non-HF individuals. *P , 0.001 vs. ‘No HF’, †P , 0.001 vs. HFpEF. The boxplot represents median and inter-
quartile range (IQR) with Tukey-style whiskers extending to a maximum of 1.5× IQR beyond the box.

Table 2 Characteristics of the left-ventricular end-diastolic pressure –volume relationship

No HF HFpEF HFrEF (n 5 79) P P P

(n 5 14487) (n 5 215) No HF vs. No HF vs. HFpEF vs.
HFpEF HFrEF HFrEF
...............................................................................................................................................................................
LV capacitance (LV EDVI20, mL/m2) 53.5 (45.2–63.0) 51.0 (42.7–62.3) 69.7 (53.3–85.3) 0.027 ,0.001 ,0.001
Stiffness coefficient b (2) 5.94 (5.92–5.98) 6.16 (6.11–6.29) 5.99 (5.94–6.11) ,0.001 ,0.001 ,0.001
a (×1011) 2.3 (0.7–7.5) 0.7 (0.2– 3.4) 0.3 (0.0– 1.3) ,0.001 ,0.001 ,0.001

LV EDVI20: LV end-diastolic volume at an end-diastolic pressure of 20 mmHg indexed to body surface area.

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 LV EDPVR in a large-scale, population-based cohort 1811

Association between risk factors
and left-ventricular end-diastolic
pressure –volume relationship
In participants without HF, the presence of risk factors for HF (age,
female gender, hypertension, diabetes, and obesity) was associated
with a steeper LV EDPVR (i.e. an increased stiffness coefficient b,
see Table 3). However, a lower LV end-diastolic capacitance (i.e. a
lower EDVI20) was only associated with increasing age and female
gender (Table 4). Dyslipidaemia, obesity, smoking, and impaired re-
nal function were associated with a higher EDVI20 (i.e. a rightward
shift of the LV EDPVR, Table 4).
Association between left-ventricular
end-diastolic pressure –volume
relationship and all-cause mortality
In participants without HF, both EDVI20 and stiffness coefficient b
were associated with the time to death (both P , 0.001). The effect
plot showed a U-shaped relation between EDVI20 and hazard ratio
of all-cause mortality, such that lower and higher values for EDVI20
were associated with a higher hazard-ratio for all-cause mortality
(Figure 3A). The stiffness coefficient b showed a rather exponential
relationship with low values associated with low hazard ratios and
high values with high hazard ratios for all-cause mortality (Figure 3B).
Discussion
We found that (i) a fairly low number of participants in this
large-scale, cross-sectional study fulfilled clinical and echocardio-
graphic criteria for HFrEF (0.53%) and HFpEF (1.45%), (ii) these sub-
groups showed a typical risk-factor profile and a substantially
increased all-cause mortality rate, (iii) the non-invasively assessed
LV EDPVR was shifted rightward in HFrEF and leftward in HFpEF,
while the stiffness coefficient b was increased in HFpEF and to a less-
er extent also in HFrEF, (iv) the presence of typical HF risk factors in
non-HF individuals was associated with increased b, but with diver-
ging effects on LV capacitance, and (v) subtle alterations of the LV
EDPVR were associated with higher hazard ratios for all-cause mor-
tality in non-HF individuals.

Table 3 Multivariable linear regression for Prevalence of heart failure and

stiffness-coefficient b in participants without heart all-cause mortality
failure The overall prevalence of HF in the current study was 1.98%. This
Beta (95% conficence interval) P-value rate is in the lower range of what was found in population-based
................................................................................ studies before. Reported values range from 2.2% in 2042 randomly
Age (years) 0.002 (0.002–0.003) ,0.001 selected Olmsted County residents .45 years of age,14 3.9% in the
Female gender (%) 0.018 (0.011–0.024) ,0.001 5540 participants .55 years in the Rotterdam Study,15 up to 4.9% in
Hypertension (%) 0.016 (0.009–0.023) ,0.001 5532 participants in The Cardiovascular Health Study.16 Given that
Dyslipidaemia (%) 20.001 (20.008– 0.007) 0.80 HF prevalence increases in older subjects,14,16 the low overall
Diabetes (%) 0.036 (0.023–0.049) ,0.001 prevalence in the current study is not surprising, as individuals
Obesity (%) 0.018 (0.010–0.026) ,0.001 .75 years were excluded from GHS.
Current smoking (%) 0.007 (20.001– 0.016) 0.076 Typical risk factors were present more often in both HF sub-
eGFR (mL/kg/min) 0.0001 (20.0004, 0.0002) 0.59 groups compared with ‘No HF’, with only moderate differences be-
tween HFpEF and HFrEF. HFpEF participants were older, more
The multivariable model included age, female gender, hypertension, dyslipidaemia, often female and had a higher body mass index, which well resem-
diabetes, obesity, smoking, and estimated glomerular filtration rate (eGFR).
bles previous epidemiological data on the frequency of co-
morbidities in HF.16 – 18 NT-proBNP levels and eight-year all-cause
mortality rates were higher in both HF subgroups compared with
‘No HF’, although absolute values for mortality rates were lower
Table 4 Multivariable linear regression for than in previous studies. This may relate to our rather young study
left-ventricular capacitance [log (EDVI20)] in cohort again, but also to the nature of population-based studies;
participants without heart failure while most other studies include HF patients after a hospitalization
event, our cohort included also less severe HF cases. We could not
Beta (95% confidence interval) P-value
................................................................................ detect a statistical difference in eight-year all-cause mortality rates
Age (years) 20.001 (20.001–0) ,0.001 between HFpEF and HFrEF. This is in line with previous studies,19
Female gender (%) 20.250 (20.258– to 20.242) ,0.001 although other authors report lower rates in HFpEF compared
Hypertension (%) 0.003 (20.006–0.012) 0.50 with HFrEF.17,20
Dyslipidaemia (%) 0.014 (0.005–0.023) 0.002
Diabetes (%) 0.010 (20.006–0.026) 0.21 Left-ventricular end-diastolic
Obesity (%) 0.109 (0.099–0.118) ,0.001 pressure– volume relationship
Smoking (%) 0.030 (0.020–0.040) ,0.001
In HFrEF, we found a rightward shift of the LV EDPVR, which indi-
eGFR (mL/kg/min) 0.004 (0.003–0.004) ,0.001
cates increased LV capacitance and reveals the dilative remodelling
process of this disease. The higher stiffness coefficient b in HFrEF
The multivariable model included age, female gender, hypertension, dyslipidaemia,
diabetes, obesity, smoking, and estimated glomerular filtration rate (eGFR). may reflect increased myocardial stiffness, which may result
from excessive reactive oxygen species production within

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 1812 M. Schwarzl et al.

Figure 3 Effect plots to visualize the associations of left-ventricular (LV) end-diastolic pressure– volume relationships and all-cause mortality
in individuals without heart failure (solid line) and 95% confidence interval (dashed line). The reference point (hazard ratio ¼ 1) was set to the
median value. (A) LV capacitance, that is, the LV end-diastolic volume at an end-diastolic pressure of 20 mmHg indexed to body surface area
(EDVI20), was associated with an increased hazard ratio for mortality in a U-shaped manner. (B) The association between the LV stiffness coef-
ficient b with the hazard ratio for mortality rather resembled an exponential relationship.

cardiomyocytes leading finally to myocardial fibrosis.21 Myocardial
fibrosis in turn was also associated with increased myocardial stiff-
ness before.22
The remodelling process in HFrEF can be halted or reversed by
pharmacological therapy, in particular by inhibitors of the renin –
angiotensin – aldosterone-system or beta-blockers.23 Such therapy
was present in only two-thirds of participants in the HFrEF sub-
group, which may affect the position and shape of the LV EDPVR.
In HFpEF, we found an increased stiffness coefficient b and a left-
ward shift of the LV EDPVR. The latter is currently conceived to be a
hallmark in the pathophysiology of HFpEF.2 It leads to elevated LV
filling pressures at a given chamber volume,24 and has been reported
in the majority of studies including HFpEF patients.10,25 However,
also other factors contribute to the complex HFpEF syndrome in-
cluding altered myocardial relaxation, impaired LV suction, ventricu-
lar dyssynchrony, atrial dysfunction, pulmonary and systemic
vascular alterations, chronotropic incompetence, right-ventricular
dysfunction, pericardial constraint, and skeletal muscle dysfunction.2
The magnitude of changes seen in the present study was rather
small, though significant. However, participants were examined
only at rest, while diastolic dysfunction typically aggravates during
exercise in HFpEF.2
Interestingly, structural and functional alterations seen in HFpEF
(including increased myocardial stiffness) had been observed during
normal aging as well,2,24,26 even in subjects free from cardiovascular
disease.24,26 In this respect, it is notable that the leftward shift of the
LV EDPVR in the present study was no longer significant, when stat-
istical tests were adjusted for age and gender, while the increase in
stiffness coefficient b persisted. This reflects that other factors on
top of what is seen with normal aging may alter myocardial proper-
ties and determine the transition from asymptomatic diastolic dys-
function to overt HFpEF.26
Finally, our findings indicate that non-invasive estimation of the LV
EDPVR is capable to detect alterations in HFrEF and HFpEF patients
and thereby extends previous findings in 65 patients4 to a large
population sample.
Association of left-ventricular capacitance
and left-ventricular stiffness with risk
factors for heart failure in non-heart
failure individuals
The other main finding in our study relates to effects of HF risk fac-
tors on the shape and position of the LV EDPVR in non-HF indivi-
duals. Risk factors for HF were in general associated with an
increased stiffness coefficient b already in individuals without HF.
The position of the EDPVR was associated with the presence of
risk factors in a non-uniform way; while a leftward shift of the
EDPVR was only found with increasing age and female gender, all
other risk factors were associated with a rightward shift of the
EDPVR in non-HF individuals.
This is well in line with previous invasive27 and with previous non-
invasive cross-sectional28,29 and longitudinal24 data, showing that
ventricular stiffness increases with normal aging. Borlaug et al.24
found that both end-systolic and end-diastolic stiffness increased
over time (4.0+0.3 years), despite a decrease in blood pressure.
The increase in end-diastolic stiffness was higher in women than
in men. Together with our data, this highlights the phenomenon
termed ‘cardiac aging’, which increases the susceptibility for the de-
velopment of HFpEF in particular in older, female subjects.2 Interest-
ingly, weight gain accelerated changes seen during ‘cardiac aging’ in
women, whereas a loss of weight prevented the age-related increase
of LV stiffening.30 We also found an association between the stiff-
ness coefficient b and metabolic factors such as obesity and
diabetes.
Also the presence of hypertension was associated with an in-
creased stiffness coefficient b in the present study. This is in line
with another study investigating the EDPVR in a population-based

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 LV EDPVR in a large-scale, population-based cohort
sample.10 The authors report an increased stiffness coefficient in the
presence of hypertension, which was more pronounced in a HFpEF
subgroup. Other risk factors were not investigated. The authors
speculated that progressive deterioration of diastolic function de-
termines the path from hypertensive heart disease to HFpEF. Wohl-
fahrt et al.31 elegantly separated arterial load into a pulsatile and
a resistive component and demonstrated that a combined chronic
increase of both components correlated with age-related LV
stiffening.
Only few studies are available investigating the effect of risk fac-
tors on the position of the EDPVR. One study found a progressive
rightward shift with an increasing number of risk factors.32 We re-
port consistent data showing that an increase in LV capacitance is
associated with the presence of dyslipidaemia, obesity, smoking,
or impaired renal function. However, while Abramov et al.32 inves-
tigated a HFpEF cohort, we extend this finding to non-HF indivi-
duals. The only study investigating the position of the LV EDPVR
in a population-based sample10 reported a leftward shift of the
EDPVR in the presence of hypertension. We did not find an associ-
ation between LV capacitance and the presence of hypertension.
The discrepancy may relate to the different age distribution in
both populations.
Taken together, we found changes consistent with ‘cardiac aging’
in non-HF individuals, as the stiffness coefficient b increased and LV
capacitance decreased with age and female gender. The presence of
other risk factors was associated also with a higher stiffness coeffi-
cient, but with an increase of LV capacitance. One may thus hy-
pothesize that risk factors per se induce molecular alterations,
which lead to increased myocardial stiffness already in non-HF indi-
viduals. However, whether the LV will undergo dilative remodelling
(i.e. a rightward shift of the EDPVR) or concentric remodelling (i.e.
a leftward shift of the EDPVR) is not per se a matter or risk factors.
Strengths and limitations
The strength of the current study is the application of non-invasive
EDPVR estimation in the largest population so far (.15 000 indivi-
duals). For the first time, this involves information on non-HF indi-
viduals in a population-based study. The nature of observational,
epidemiological studies, however, implies a lack of mechanistic
information. We could only report on associations that are
hypothesis-generating rather than hypothesis-testing. Some changes
were of small magnitude, though significant due to the large sample
size and may not translate into a clinically significant condition. Their
biological relevance needs to be clarified in further studies. Of note,
since the estimation of LV EDPVR in this study is subject to meas-
urement errors (echocardiography), which in turn increases vari-
ance, the associations may appear weaker than they truly are. On
the other hand, with each estimation step, a potential increase in un-
certainty is introduced that may limit the veracity of our findings.
The non-invasive, single-beat estimation of the LV EDPVR has
been applied in a population-based study before,10 but it relies on
many assumptions. First, it suggests a common shape of the LV
EDPVR, which appears questionable. The gold standard to assess
the LV EDPVR is a multi-beat analysis of continuous LV pressure
and volume recordings during a change in loading conditions. This
is typically performed using a conductance catheter and a vena
cava balloon catheter to reduce preload transiently. Such invasive
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1813
measurements, however, are not feasible in .15 000 individuals.
A direct comparison of both methods showed tight correlations
in the past, although small but systematic deviations were present
at low and high pressures. 33 Second, there is ongoing debate,
whether EDP can be calculated solely from E/e′ -measurements.
Although older studies demonstrate a close (r ¼ 0.87)34 or moder-
ate (r ¼ 0.64)11 correlation between E/e′ -ratios and LV filling pres-
sures, newer studies did not confirm these findings both in systolic
HF patients (r ¼ 0.18)35 and subjects with normal EF (r ¼ 0.23).36
This is of particular interest, as E/e′ plays a central role in calculating
the EDPVR in the present study. To confirm our findings, we used an
alternative equation to derive EDP (EDP ¼ 1.9 + 1.24 × E/e′ )34
and found qualitatively similar results (see Supplementary material
online). Third, the EDP was derived from E/e′ measurements at
the lateral mitral valve annulus and was not available in participants
with atrial fibrillation during echocardiographic examination.
The GHS is a population-based study with very little inclusion and
exclusion criteria. However, some bias may still be present regard-
ing participant selection. First, participants were young with respect
to HF (,75 years) and most of them were white Caucasian. The re-
sults may thus not be transferable to older or other ethnic groups.
Secondly, people unable to attend the study centre were excluded
from GHS, such that, in particular, multimorbid participants may be
underrepresented. Thirdly, there may be ‘volunteer bias’ as indivi-
duals that agree to participate in a study are in general healthier,
which in particular may cause an underestimation of age-related
effects.24
Finally, a major limitation relates to the lack of specificity for the
HF definitions used in the present study. Data on the HF subgroups
clearly have to be interpreted keeping in mind that differential diag-
noses for dyspnoea had been possibly included. However, it is strik-
ing that typical alterations of the LV EDPVR were detectable in these
subgroups despite the above-mentioned limitations. Moreover, the
low-specific but high-sensitive definition of HF in turn should have
excluded any HF cases from the ‘No HF’ subgroup, which strength-
ens conclusions drawn from data on this subgroup.
Conclusion
We found a typical risk factor profile and typical alterations of the
LV EDPVR in HFpEF and HFrEF subgroups within a large-scale,
population-based cohort. In individuals without HF, cardiovascular
risk factors were associated with an increased stiffness coefficient
b, while the LV EDPVR was shifted leftward with age and female
gender, but rightward with all other risk factors. Thus, the presence
of risk factors alone in non-HF individuals relates to alterations of
the LV EDPVR. These alterations were associated with a higher
risk of death in non-HF individuals.
Supplementary material
Supplementary material is available at European Heart Journal online.
Authors’ contributions
F.O.: Performed statistical analysis; T.M., P.S.W., M.B., K.J.L., N.P.,
M.E.B., S.B., D.W.: Handled funding and supervision; M.S., F.O.:
 1814
Acquired the data; M.S., F.O., T.Z., M.S., P.M.B., T.M., P.S.W., M.B.,
K.J.L., N.P., M.E.B., S.B., D.W.: Conceived and designed the research;
M.S., D.W.: Drafted the manuscript; M.S., F.O., T.Z., M.S., P.M.B.,
T.M., P.S.W., M.B., K.J.L., N.P., M.E.B., S.B., D.W.: Made critical revi-
sion of the manuscript for key intellectual content.
Funding
The Gutenberg Health Study (GHS) was supported by the government
of Rheinland-Pfalz (‘Stiftung Rheinland Pfalz für Innovation’, contract No.
AZ 961-386261/733), the research programs ‘Wissen schafft Zukunft’
and ‘Schwerpunkt Vaskuläre Prävention’ of the Johannes Gutenberg-
University of Mainz, and its contract with Boehringer Ingelheim and
Philips Medical Systems including an unrestricted grant for the GHS.
Conflict of interest: none declared.
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