Association among epicardial fat, heart rate recovery and circadian blood pressure variability in patients with hypertension

Study population

This cross-sectional, observational single-center cohort study included 358 consecutive
patients who simultaneously underwent 24-hour ABPM, an exercise treadmill test and
echocardiography between January 2010 and March 2015. Inclusion criteria were: 18–80
years of age, normal renal function and for women to be on a regular menstrual cycle.
Exclusion criteria were: any systemic disease such as significant liver disease, neurologic
disorders or malignant disease; secondary hypertension; valvular heart disease; a
positive treadmill test; a history of heart failure; a history of acute coronary syndrome;
myocar dial infarction or any revascularization procedure. Demographic characteristics
recorded at the first visit included age, gender, height, weight, current medications,
smoking history and other comorbidities. Blood was drawn for measurement of total
serum cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol,
triglycerides, blood glucose, creatinine, uric acid, and high sensitivity C-reactive
protein (hs-CRP). Body mass index (BMI) was calculated as the ratio of weight in kilograms
to height in square meters. This study was approved by the Kosin University International
Review Board. All patients were required to provide written informed consent to participate.

Blood pressure measurement and ambulatory blood pressure monitoring

Office BP measurements were measured twice at 5-min intervals using a mercury sphygmomanometer.
Noninvasive 24-hour ABPM was performed on each patient’s non-dominant arm using an
automatic oscillometric device (TONOPORT V, PAR Medizintechnik, Berlin, Germany) on
a normal working day. Patients were generally asked to refrain from fast exercise
or stop taking the antihypertensive medications before 48 h. All subjects were instructed
to rest or sleep between 10:00 PM and 7:00 AM (nighttime) and to continue their usual
activities between 7:00 AM and 10:00 PM (daytime). The accuracy of the device was
checked against the standard auscultatory method to assure the difference in BP measurements
between methods did not exceed 5 mmHg. The device was set to obtain BP readings at
20-min intervals during the daytime and at 40-min intervals during the nighttime.
Only 24-hour recordings that included at least 80 % successful recordings were accepted
as valid. Each ABPM dataset was first automatically scanned to remove artifactual
readings according to preselected editing criteria. The following ABPM parameters
were evaluated: 24-hour mean systolic and diastolic BP levels, daytime mean systolic
and diastolic BP levels, nighttime mean systolic and diastolic BP levels and BP variability
assessed by standard deviation (SD). Additionally, the magnitude of the nocturnal
decline in BP (? nocturnal decline) was calculated as follows: daytime average BP
minus nighttime average; the percentage change in BP from day to night (% day – night
BP) was calculated as: (daytime BP – nighttime BP)?×?100/daytime BP.

Diagnosis of hypertension

Following the recommendations of the European Society of Hypertension, 18] a normotensive state was defined as a mean daytime ambulatory systolic and diastolic
BP??135/85 mmHg by ABPM, associated with an office BP??140/90 mmHg. True hypertension
was assigned if the average daytime BP was higher than 135/85 mmHg and the average
nighttime BP was above 120/75 mmHg. In addition, the hypertensive subjects who had
reduction in BP??10 % change from daytime to nighttime period were defined as “non-dippers”,
and the hypertensive subjects who had a reduction in BP???10 % change from daytime
to nighttime were considered “dippers”. Patients were classified according to the
ABPM; 147 patients had hypertension and the dipping pattern (dippers), 140 patients
had hypertension and a non-dipping pattern (non-dippers) and 71 were normotensive
controls.

Echocardiographic measurement

Standard 2-dimensional echocardiography were performed on all subjects while lying
in the left lateral decubitus position using a 3.5-MHz transducer (Philips iE33, Philips
Medical Systems, Bothell, WA, USA) and the echocardiography examiners were blinded
to patient information. Measurements of the thickness of the interventricular septum
and posterior wall, the diameter of the left ventricle (LV) cavity, and the LV mass
index (LVMI) were performed according to criteria outlined by the American Society
of Echocardiography 19]. Echocardiographic assessments of EFT, defined as the echo-free space between the
outer wall of the myocardium and the visceral layer of the pericardium, were measured
perpendicularly from the free wall of the right ventricle at the end-systole in three
cardiac cycles according to the method we previously described (Fig. 1) 20]. Because one of the critical issues in EFT measurement is the inconsistency in the
measurement location, and mean EFT was averaged from the images of the parasternal
long axis, parasternal short axis and apical 4 chamber view. Independent offline measurement
of EFT was performed by two cardiologists (DJ Kim and KI Cho) who were unaware of
the clinical data in the first 50 continuous patients, which was repeated at least
twice. A reliability analysis using intra-class correlation coefficient was performed
to obtain the intra-observer and inter-observer variability. The intra- and inter-observer
variability of the EFT was 3.3 and 5.8 %, respectively.

Fig. 1. Echocardiographic assessments of EFT, defined as the echo-free space between the outer
wall of the myocardium and the visceral layer of the pericardium, were measured perpendicularly
from the free wall of the right ventricle at end-systole in the parasternal long axis
view

Exercise treadmill testing

On the same day as the echocardiographic examination, patients underwent symptom-limited
exercise stress testing (GE CASE T2100; GE Medical Systems, Milwaukee, WI, USA) according
to the protocol by Bruce et al. 21]. BP was measured with an automated BP monitor (Suntech Tango; Suntech Medical, Morrisville,
NC, USA) throughout the treadmill test using the same arm as resting BP was measured
on. Twelve-lead electrocardiography was monitored continuously and was printed at
a paper speed of 25 mm/s; measurements of HR and BP were recorded at the end of each
3-min stage, at peak exercise and at 1-min intervals throughout recovery. The participants
continued to exercise until volitional fatigue or if their HR exceeded 95 % of estimated
maximal HR (220 bpm – age). Total exercise time was also recorded. Functional capacity
was estimated in metabolic equivalents (METs) on the basis of the spceed and grade
of the treadmill 22]. During the recovery phase, the subjects continued to walk for 60 s at a speed of
1.5 mph, and then they sat down for 3 min with continued monitoring of BP, HR and
heart rhythm. The value for the HRR was defined as the decrease in the HR from peak
exercise to one minute after the cessation of exercise. An abnormal value for the
HRR was defined as???12 beats/min in accordance with previous studies 10].

Statistical analysis

Statistical analyses were performed with the commercially available computer program
SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Data are presented as mean?±?standard
deviation for continuous variables and their percentages (%) if the data are categorical.
The Mann – Whitney U test was used for continuous variables and the chi-square test
was used for categorical data. The normality of data was tested using the Kolmogorov–Smirnov
test. Parameter differences among the three groups were evaluated using a one-way
ANOVA for normally distributed variables or the Kruskal–Wallis test for non-normally
distributed variables. Relationships between variables were examined with Pearson
correlation coefficients. The cutoff value of EFT for predicting blunted HRR with
corresponding sensitivity and specificity was estimated by receiving operator characteristic
(ROC) curve analysis. Multivariate logistic regression models for blunted HRR were
built to determine which variables were independently associated with this status.
A two-tailed p??0.05 was considered to be statistically significant.