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Received: 2 January 2018 Revised: 20 February 2018 Accepted: 28 February 2018 DOI: 10.1111/jch.13271
ORIG INAL PAPER
Genetically determined pattern of left ventricular function in normal and hypertensive hearts Attila Kovács MD, PhD1
| Andrea Ágnes Molnár MD, PhD1 | Márton Kolossváry
MD1 | Bálint Szilveszter MD, PhD1 | Alexisz Panajotu MD1 | Bálint Károly Lakatos MD1 | Levente Littvay PhD2 | Ádám Domonkos Tárnoki MD, PhD3,4 | Dávid László Tárnoki MD, PhD3,4 | Szilard Voros MD5 | György Jermendy MD, PhD, DSc6 | Partho P. Sengupta MBBS, MD, DM7 | Béla Merkely MD, PhD, DSc1 | Pál MaurovichHorvat MD, PhD, MPH1 1 MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary 2
Central European University, Budapest, Hungary 3 Hungarian Twin Registry, Budapest, Hungary 4 Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary 5
Global Genomics Group, Atlanta, GA, USA
6
III. Department of Internal Medicine, Bajcsy-Zsilinszky Hospital, Budapest, Hungary 7 West Virginia University School of Medicine, Morgantown, WV, USA
Correspondence Attila Kovács MD, PhD, MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary. Email:
[email protected]
We sought to assess the inheritance of left ventricular (LV) function using speckle- tracking echocardiography and the impact of hypertension on modifying the genetically determined pattern of contraction in a population of twins. We recruited 92 Caucasian twin pairs, including 74 hypertensive (HTN) siblings. Beyond standard echocardiographic protocol, a speckle-tracking analysis was performed, including global longitudinal strain (GLS). Systolic function, as assessed by ejection fraction, showed moderate heritability (61%); however, GLS showed higher and dominant heritability (75%). Heterogeneity models revealed that there were no differences between the HTN and non-HTN subjects regarding the heritability of GLS. However, the heritability estimates of diastolic function parameters, including early diastolic strain rate, were low. LV systolic biomechanics is highly heritable. GLS shows dominant heritability, despite the presence of early-stage hypertensive heart disease. Early diastolic parameters are rather determined by environmental factors. These findings suggest the presence of a genetic framework that conserves systolic function despite the expression of diastolic dysfunction and may underlie the phenotypic progression towards heart failure with preserved ejection fraction.
Funding information The initial part of this study was supported by a grant from the EFSD New Horizons Program to György Jermendy. This work was also supported by the National Research, Development and Innovation Office (NKFIH) of Hungary (“National Heart Program” NVKP_16-1-2016-0017 to Béla Merkely), by the Ministry of Human Capacities (“New National Excellence Program” ÚNKP-17-4 to Attila Kovács) and by the Arrhythmia Research Foundation.
Kovács, Molnár, Merkely and Maurovich-Horvat contributed equally to this manuscript.
J Clin Hypertens. 2018;20:949–958.
wileyonlinelibrary.com/journal/jch ©2018 Wiley Periodicals, Inc. | 949
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1 | I NTRO D U C TI O N
2.2 | Study protocol
More than 26 million people worldwide have heart failure, and recent
Past medical history, lifestyle habits, and anthropometric param-
studies have shown that approximately 50% of them have preserved
eters, such as height and body weight, were recorded. The physi-
ejection fraction (HFpEF).1 The pathophysiologic background of the
cal examination included a blood pressure measurement, a 12-lead
phenotypic expression of HFpEF is not well understood. Elevated
ECG, and an assessment of potential symptoms and physical signs
blood pressure represents the most important cause of HFpEF by
of any cardiovascular disease. Only siblings with a positive medical
deteriorating myocardial structure and function.1,2 However, the un-
history of hypertension who were on antihypertensive treatment
derlying genetic pathways that conserve ejection fraction during the
were entered into the statistical analysis and were compared to non-
early development of hypertension-related diastolic dysfunction are
hypertensive (HTN) subjects.8 Two experienced cardiologists (AK and AÁM, with 7 and 9 years
less investigated. While the most widely used measure of cardiac performance
of experience, respectively) who were blind to the zygosity of the
is ejection fraction, previous studies have produced conflicting
twins performed the transthoracic echocardiography (iE33 system,
3,4
S5-1 transducer). LV end-diastolic and end-systolic volumes and ejec-
results regarding its heritability.
Advanced imaging techniques,
such as speckle-tracking echocardiography, provide novel insights into left ventricular (LV) biomechanics and have a higher sensitivity
tion fraction were calculated using the biplane Simpson method.9 The Devereux formula was used to quantify LV mass. Parameters of
to detect subclinical stages of different cardiac diseases. Proper
LV diastolic function (ie, mitral inflow velocities, pulsed-wave tissue
study models along with more accurate measurements may reveal
Doppler imaging of mitral medial and lateral annular velocities) were
5
the real impact of genetics on LV function. Twin studies are widely used to characterize the interactions of genetic and environmen-
determined according to current guidelines.10 Body surface area (BSA) was calculated using the Mosteller formula.11
tal factors.6 Nevertheless, no twin studies have been previously performed to assess the heritability of LV function using speckle- tracking imaging.
2.3 | Speckle-tracking analysis
The present study was conducted to determine the heritability
Beyond conventional echocardiographic measurements, the pro-
of LV function by assessing advanced echocardiographic parameters
tocol included the acquisition of high-quality images appropriate
in a cohort of Caucasian twins. We aimed to investigate whether
for 2-dimensional speckle-t racking analysis. Parasternal short-a xis
the presence of hypertension modifies the genetically determined
views of the mitral valve, papillary muscle, and apical levels as well
pattern of cardiac biomechanics.
as apical 4-chamber, 2-chamber, and long-a xis views were acquired for speckle tracking. The targeted frame rate was between 60 and 90 FPS, and adequate focus position, depth, sector size, and
2 | M E TH O DS
time-g ain compensation settings were used. Raw data were ex-
2.1 | Study population
ported to a standalone workstation for off-line analysis with commercially available software (2D Cardiac Performance Analysis
The BUDAPEST-G LOBAL study (Burden of Atherosclerotic
v1.2). A single-b lind operator (AK) performed the speckle-t racking
Plaques Study in Twins—Genetic Loci and the Burden of
analysis. After manual delineation of the endocardial surface, the
Atherosclerotic Lesions) is a prospective, single-center, classical
software tracked the region of interest throughout 3 consecutive
twin cohort study that was established to assess the effects of
cardiac cycles. If the operator detected low endocardial tracking
genetic and environmental factors on different cardiovascular
fidelity, the border was realigned and the calculation was repeated
phenotypes using multiple imaging modalities and haemodynamic
a maximum of 3 times. Segments with poor tracking quality, as
6
measurements. The twin participants were recruited from the 7
Hungarian Twin Registry. From April 2013 to July 2014, 101 twin
determined visually based on the pattern or the lack of explicit end-s ystolic peak value of the strain curve, were excluded. Peak
pairs were investigated. Details of the enrolment and exclusion
systolic strains of the 16 LV segments averaged over 3 cardiac
criteria were previously published. 6 In brief, twin pairs with ob-
cycles were used to calculate the corresponding global values.
structive coronary artery disease (indicated by coronary CT an-
Global circumferential strain (GCS) and global radial strain (GRS)
giography), any form of cardiomyopathy, severe valvular heart
were quantified using the parasternal short-a xis views. In addition,
disease, or symptoms of heart failure were excluded. All of the
we determined the apical counter-clockwise and basal clockwise
twin siblings provided written consent for participation. The study
rotations by averaging the 4 and 6 segmental values, respectively;
design complied with the Declaration of Helsinki and the protocol
and we subsequently determined their net difference (ie, LV twist).
was approved by the Scientific and Research Ethics Committee
Apical views were used to assess global longitudinal strain (GLS)
of the National Medical Research Council [Approval number:
and systolic strain rate (LSrS) along with early (LSrE) diastolic
58401/2012/EKU (828/PI/12), amendment-1: 12292/2013/EKU
strain rate values. Subjects with fewer than 10 available segmen-
(165/2013)].
tal values were not included in the statistical analysis (n = 9 pairs).
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KOVÁCS et al.
2.4 | Statistical analysis Continuous variables are expressed as the mean ± standard devia-
show a significant decrease in fit, then the ACE or ADE models were selected, and the heterogeneity models were discarded, indicating a failure to demonstrate differences in A, C, D, and E between HTN
tion (SD), whereas categorical variables are expressed as frequen-
and non-HTN subjects. All calculations were adjusted for age, sex,
cies and percentages. The monozygotic (MZ), dizygotic (DZ) and
and hypertension. Log likelihood-based 95% confidence intervals
HTN and non-HTN groups were compared using Student’s t-tests
(CIs) were calculated for all estimated parameters. All calculations
and Chi-square tests. Correlations were calculated using Pearson’s
were performed using R version 3.2.1. Twin modeling was per-
correlation coefficients. Descriptive statistics and correlations were
formed using OpenMx version 2.3.1. A P value lower than .05 was
calculated using SPSS Statistics, version 22 (IBM, Armonk, NY, USA).
considered significant.
2.5 | Twin statistics
2.6 | Intra-and interobserver variability
Phenotypic differences between individuals are caused by genetic
The reproducibility of the speckle-tracking measurements was as-
and environmental factors. Genetic factors can be additive (A),
sessed by 2 experienced readers (AK and AÁM) based on 10 ran-
representing polygenic inheritance, or dominant (D), representing
domly selected MZ twin pairs and 10 randomly selected DZ twin
dominant allele interactions. Environmental factors can be common
pairs using the intra-class correlation coefficient (ICC). Coefficient
(C), which are shared between siblings, or unique (E), causing within-
values were interpreted as follows: 1.00-0.81: excellent; 0.80-0.61:
family variation. Phenotypic variation is a result of these latent vari-
good; 0.60-0.41: moderate; 0.40-0.21: fair; and 0.20-0.00: poor.13
ables, ie, A, C, D and E.
The results are shown in Table S1.
In classical twin studies, the amount of genetic similarity between the siblings is known. On average, MZ twins share 100% of their genome, while DZ twins share half. Based on Mendelian genet-
3 | R E S U LT S
ics, this results in MZ siblings sharing 100% of their A and D genetic factors, while DZ twins share only 50% and 25% of their A and D
Of the 202 twins enrolled in the BUDAPEST-GLOBAL study, 184
latent genetic variables, respectively. Regarding environmental fac-
twin siblings were included in the current investigation. In total, 18
tors, both MZ and DZ twins share 100% of their common environ-
twins (ie, 9 pairs) were excluded due to insufficient image quality.
mental factors but none of their unique ones. Using this information,
Our twin cohort represented a middle-aged (57 ± 9 years, 65%
the variance and the covariance between the siblings can be decom-
female), Caucasian population (Table 1). The prevalence of hyper-
posed using structural equation modeling.12 In MZ twins, the vari-
tension, diabetes mellitus, dyslipidemia, and smoking was represen-
ance is the sum of the A, C, D, and E latent factors, while the co-t win
tative of the broader community.14 DZ twin pairs were older and had
covariance is the sum of the A, C, and D latent variables. As DZ twins
a higher heart rate. Early diastolic mitral inflow velocity was higher
share only 50% of their genome, the covariance is the sum of 0.5*A,
in MZ twin pairs. All other demographic and echocardiographic pa-
C and 0.25*D latent factors, while the variation is caused by A, C, D,
rameters were similar between the MZ and DZ pairs.
and E. Based on maximum likelihood estimates, A, C, D, and E can be
Seventy-four siblings had been previously diagnosed with ar-
estimated. The C and D factors are confounded in the data of same-
terial hypertension. Despite optimal antihypertensive medication,
sex DZ pairs reared together; thus, only ACE or ADE models can be
HTN siblings had higher systolic and diastolic blood pressure values
calculated separately. Full ACE or ADE models were compared based
than the non-HTN siblings (Table 2). HTN siblings were older and
on minus 2 log likelihood (−2LL) values. The better-fitting full model
had higher BMI. The average LV mass values were within the normal
with the smaller −2LL value was selected. The likelihood ratio test
range; however, HTN siblings had significantly higher LV mass and
was used to assess the fit of submodels compared to the full model.
mass index. Left atrial volumes were normal and similar between the
If the fit did not decrease significantly, the more parsimonious sub-
groups. LV systolic function, as indicated by ejection fraction and
model was selected. In the case of ACE models, if both the AE and
GLS, was maintained in the HTN and non-HTN siblings. GCS was
CE models showed no significant decrease in fit, then the model
statistically, but not clinically significant reduced in HTN siblings.
showing less deterioration in fit (smaller −2LL difference) than the
The E/A ratio, tissue Doppler measurements and, notably, early di-
full ACE model was selected. For ADE models, the DE submodel was
astolic longitudinal strain rate were all impaired in the HTN group,
not calculated because a model considering dominant, but having no
indicating diastolic dysfunction. In summary, HTN siblings presented
additive genetic effects, is highly unlikely.
with early-stage hypertensive heart disease (HHD) without relevant
To assess whether the contributions of genetic and environmen-
morphological alterations or systolic dysfunction (Table 2).
tal factors were equal in HTN and non-HTN subjects, we calculated
By comparing cardiac morphology and systolic function in the
quantitative heterogeneity models by grouping subjects based on
MZ and DZ twin pairs, we found that the MZ twins were more similar
the presence of HTN. The heterogeneity models were tested against
to each other than were the DZ twins based on the correlation coef-
the corresponding full ACE or ADE models based on the likelihood
ficient values (Figure 1 and Table S2). Structural equation modeling
ratio test. If the more parsimonious ACE or ADE models did not
revealed a moderate-to-high heritability of LV structural parameters
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KOVÁCS et al.
952
TA B L E 1 Demographic characteristics and echocardiographic parameters of the study population Variables
Total (n = 184)
MZ (n = 108)
DZ (n = 76)
P
Demographic, basic hemodynamic characteristics and medical history Female (n)
120 (65.2%)
68 (63.0%)
52 (68.4%)
.444
Age (y)
56 ± 9
54 ± 10
58 ± 8
.006
Height (cm)
166 ± 10
166 ± 10
167 ± 9
.377
Weight (kg)
76 ± 16
75 ± 16
77 ± 16
.550
BMI (kg/m )
27.4 ± 4.8
27.3 ± 4.5
27.6 ± 5.3
.736
BSA (m2)
1.86 ± 0.23
1.85 ± 0.24
2.00 ± 0.21
.554
Natal weight (g)
2338 ± 597
2272 ± 585
2433 ± 607
.094
SBP (mm Hg)
140 ± 20
139 ± 19
141 ± 22
.499
DBP (mm Hg)
86 ± 12
85 ± 12
86 ± 12
.498
HR (1/min)
71 ± 11
70 ± 11
74 ± 11
.025
HT (n)
74 (40.2%)
41 (38.0%)
33 (43.4%)
.457
DM (n)
15 (8.2%)
10 (9.3%)
5 (6.6%)
.513
DLP (n)
76 (41.3%)
40 (37.0%)
36 (47.4%)
.161
Smoking (n)
65 (35.3%)
34 (31.5%)
31 (40.8%)
.193
157 ± 49
155 ± 45
159 ± 54
.577
LVMi (g/m )
83 ± 21
83 ± 19
84 ± 23
.820
EDV (mL)
91 ± 28
91 ± 28
92 ± 27
.753
EDVi (mL/m )
49 ± 12
49 ± 11
49 ± 12
.781
ESV (mL)
38 ± 15
38 ± 15
38 ± 17
.871
ESVi (mL/m )
20 ± 7
20 ± 7
20 ± 8
.758
LAV (mL)
44 ± 18
45 ± 18
42 ± 17
.191
24 ± 9
25 ± 9
22 ± 9
.083
EF (%)
59 ± 7
59 ± 6
60 ± 8
.181
GLS (%)
−22.0 ± 2.6
−22.0 ± 2.2
−21.9 ± 3.0
.661
LSrS (1/s)
−1.13 ± 0.13
−1.13 ± 0.11
−1.13 ± 0.15
.670
GCS (%)
−25.9 ± 3.0
−25.7 ± 2.6
−26.2 ± 3.5
.260
GRS (%)
37.8 ± 5.9
38.1 ± 6.6
37.4 ± 4.7
.457
Basal rotation (°)
−4.9 ± 1.7
−4.8 ± 1.7
−5.0 ± 1.8
.672
Apical rotation (°)
6.9 ± 2.3
6.9 ± 2.1
6.8 ± 2.6
.634
Twist (°)
11.8 ± 3.0
11.8 ± 2.9
11.7 ± 3.2
.910
E wave (m/s)
0.72 ± 0.15
0.74 ± 0.16
0.70 ± 0.12
.035
E/A
1.11 ± 0.39
1.14 ± 0.40
1.07 ± 0.36
.243
DCT (msec)
208 ± 53
207 ± 52
209 ± 55
.742
LSrE (1/s)
1.25 ± 0.35
1.23 ± 0.34
1.27 ± 0.36
.501
E(m) (m/s)
0.09 ± 0.03
0.09 ± 0.03
0.09 ± 0.03
.335
E(l) (m/s)
0.12 ± 0.03
0.12 ± 0.03
0.12 ± 0.04
.892
E/E(m)
8.8 ± 3.0
8.9 ± 3.1
8.7 ± 2.8
.607
E/E(l)
6.6 ± 2.3
6.8 ± 2.3
6.4 ± 2.2
.217
2
Morphological parameters LVM (g) 2
2
2
2
LAVi (mL/m ) Left ventricular systolic function
Left ventricular diastolic function
A, late diastolic flow; BMI, body mass index; BSA, body surface area; DBP, diastolic blood pressure; DCT, deceleration time; DLP, dyslipidemia; DM, diabetes mellitus; E, early diastolic; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; i, indexed to BSA; (l), mitral lateral annulus; LAV, left atrial volume; LVM, left ventricular mass; LSr, longitudinal strain rate; (m), mitral medial annulus; S, systolic; SBP, systolic blood pressure. Continuous variables are presented as mean ± SD, while categorical as n (%). P values represent statistical tests done between the monozygotic (MZ) and dizygotic (DZ) twin pairs.
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KOVÁCS et al.
TA B L E 2 Demographic characteristics and echocardiographic parameters of patients with and without hypertension (HTN) Variable
HTN (n = 74)
Non-HTN (n = 110)
P
Demographic, basic hemodynamic characteristics and medical history Female (n)
46 (62.2%)
74 (67.3%)
Age (y)
60 ± 8
53 ± 9
