METHODS
Study population
The study population consisted of participants of the Seventh Tromsø
Study (Tromsø7) in Norway and the Know Your Heart (KYH) study in Russia.
Both studies were cross-sectional and population-based. Tromsø7 was
conducted in the Tromsø municipality between March 2015 and October
2016, and KYH from 2015 to 2018 in Arkhangelsk and Novosibirsk. The two
studies were conducted in parallel and included questionnaires, health
examinations, and biological sample collection. During the development
phases, several aspects of data collection between the studies were
harmonized, including the echocardiography protocols. Echocardiograms
were performed in 2340 participants from Tromsø7 and 4521 from Russia.
In Tromsø7, the inclusion age range was 40 years and older, without an
upper limit, whereas KYH included participants aged 35–69 years. For
the present study, a stratified random selection of participants was
made, giving three equal-sized age groups (40–49, 50–59, and 60–69
years old). As shown in Figure 1, the sample comprised participants from
Tromsø7 (50%), Arkhangelsk (25%) and Novosibirsk (25%). A total of
1194 participants from KYH (594 women and 600 men) and 1013 participants
from Tromsø 7 (553 women and 460 men), aged 40–69 years, were selected.
Definition of study groups
Figure 1 displays a flow chart of in- and exclusion of study
participants. Individuals with cardiac disease that could impact
myocardial function were excluded from the study population. Therefore,
we excluded subjects with valvular heart disease (aortic insufficiency
grade 3 and 4); aortic valve mean pressure gradient >25
mmHg; mitral insufficiency degree 3 and 4; moderate and high-grade
mitral stenosis; history, or objective indicators of previous coronary
artery disease (classes 1.1 – 1.2.7. of Minnesota Code) or myocardial
diseases; ECG with QRS > 130 ms, EF < 45%.
Hypertension was defined as either increased systolic or diastolic BP
during the visit or the current use of antihypertensive medication. The
study population was divided into groups using the following criteria:
systolic BP ≤ 140 mmHg and diastolic BP ≤ 90 mmHg without
antihypertensive medication (group A, normotensive); systolic BP ≤ 140
mmHg and diastolic BP ≤ 90 mmHg with antihypertensive medication (group
B, controlled hypertension); systolic BP 140–159 mmHg and/or diastolic
BP >90 mmHg (group C), and systolic BP ≥ 160 mmHg (group
D). Groups C and D were defined as hypertensive irrespective of the
antihypertensive medication.
Participants were classified as taking antihypertensive medications when
self-reported to be currently taking renin-angiotensin system drugs,
beta-blockers, calcium antagonists, or diuretics.
Data collection and echocardiography in KYH and Tromsø7
The transthoracic echocardiography was performed in the left lateral
decubitus position using commercially available GE Healthcare systems:
Vivid q equipped with a 1.5–3.6 MHz sector matrix transducer in KYH
study and high-end machine E9 with single crystal matrix sector probe of
1.5–4.6 MHz in Tromsø7. From parasternal and apical views,
two-dimensional (2D) grayscale images and pulsed, continuous, and color
Doppler data were acquired. Both studies included apical four-chamber
(4CH) and two-chamber (2CH) views, while apical long-axis views (APLAX)
were only acquired in Tromsø7. 2D-images were obtained at a frame rate
of at least 50 fps. The commercial software EchoPAC (v.203, GE-Vingmed
AS, Horten, Norway) was used for strain analyses. Intra- and
inter-observer variability for conventional echocardiographic measures
were regularly assessed within both KYH and Tromsø7 reading laboratories
and compared between laboratories. Conventional echocardiography
included left ventricular systolic and diastolic volume (LV ESV; LV
EDV), stroke volume (SV), ejection fraction (EF), and left atrial volume
(LAV) measurements using the Simpson biplane method. Doppler-derived
measurements included mitral valve (MV) E, A, E/A ratio, and
deceleration time (MV DT). The M-mode was used to estimate the septal
wall thickness and myocardial mass. SV, myocardial mass, and left atrial
(LA) volume were indexed by body surface area (BSA).
Strain and strain-rate analysis
A single reader (M.K.) analyzed all strain data using the Q-analysis
function of EchoPAC. For all analyses, the peak R was set as the
endpoint of end-diastole. Aortic valve closure was defined as a
transaortic CW Doppler signal. The region of interest (ROI) was defined
by manual definition of the subendocardial border and adjustment of the
ROI width. Automated tracking was visually controlled, and suboptimal
tracking results were repeated a maximum of three times. From the 12 (or
18) segments, the following segmental values were extracted from the
strain analysis: segmental end-systolic (ES) subendocardial (endo),
mid-myocardial (myo), and epicardial strain (epi). Furthermore, the peak
systolic SR (SR S), peak SR E and SR A, and respective peak global S/SR
values for two or three apical views were extracted using the software.
Post-systolic stretching (PSS) was calculated as the difference between
the ES strain and peak diastolic strain. Segments were classified as PSS
present or absent by defining cutoff values (-1 to -3% and
> -3%).
S/SR from APLAX views was analyzed in 176 Tromsø7 participants. Based on
previous analyses of this study population, we assigned segmental groups
with similar values, that is basal septal, basal, mid, and apical
segments.
Artefact reading
Artifact detection was used to identify distorted echocardiographic
records that were to be excluded from analysis. The identification of
strain-curve artifacts was based on artifact detection by visual
assessment of the strain curves and was described in detail in a
previous publication (12) on the same study population. Strain curve
artifacts were subjectively assessed using these previously described
features and classified as (1) “blunted curves” (a reduced or even
positive strain in the start of the cycle, mirrored by a similar
curve-formation at the end of systole), (2) “diastolic mismatch” (late
diastolic strain curve significantly deviating towards 0 or positive
values compared to the late diastolic strain-curves of other segments),
and (3) “floating” (segmental strain curves with several negative and
positive peaks without correspondence with timing or configuration of
other segments). Segments with curve artifacts or apical foreshortening
were discarded. As shown in Figure 2, apical foreshortening and curve
artifacts reduced the number of echocardiograms included in the final
analysis.
Blood pressure (BP) measurements
In KYH and Tromsø7, blood pressure was measured in the sitting position
in a quiet room, either before or after the echocardiogram, but not on
the same day. The measurements were performed three times at 1-minute
intervals after an initial 2-minute seated rest. The results of the
second and third measurements were averaged and used for the analysis.
All study participants were asked about the medications they were
currently taking, and the data were coded using the Anatomical
Therapeutic Chemical (ATC) classification system. Any medications within
ATC classes C02, C03, C07, C08, or C09 were regarded as
antihypertensives.
Statistical analyses
If not stated otherwise, continuous variables are presented as mean ±
standard deviation (SD). Variables with skewed distributions are
presented as medians with quartiles (Q1–Q3). Categorical
characteristics are presented as absolute numbers and proportions (%).
Between-group differences in continuous variables were tested using
one-way analysis of variance (ANOVA) with Bonferroni post hoc tests, and
a χ2 test was used for group comparisons of
categorical variables. Multiple linear regressions were used to assess
associations between hypertension status and echocardiographic
parameters with adjustments for potential confounders (age, sex, height,
body mass index (BMI), heart rate (HR), atrial fibrillation (AF), and
KYH/Tromsø study population). All multiple regression models were run on
the sample with complete data for all covariates (n = 1707).
Statistical significance was set at p < 0.05. SPSS v28.0 (IBM
Corp.) was used for statistical analyses.
Intra-and interobserver-variability
The intra- and inter-observer variabilities have been previously
reported (12). For intra-and inter-observer variability in strain and SR
measurements, the same observer repeatedly analyzed 135 randomly
selected echocardiographic records comprising 1620 segments within 6–12
months from the initial analysis. The same data were reanalyzed by a
second experienced observer. Intra- and inter-observer values were
calculated as Bland–Altman limits of agreement for segments and
discarding segments with curve-artifacts.