Impact of blood pressure changes on myocardial work indices in hypertensive patients in a day

Abstract Evaluating left ventricular function through instantaneous left ventricular deformation parameters might not always be accurate for patients with high fluctuations in blood pressure value due to afterload dependence. Myocardial work (MW) is a more advanced tool that combines global myocardial longitudinal strain (GLS) with LV (left ventricular) systolic pressure. The purpose of this study was to investigate the effect of blood pressure changes on MW indices in the population with normal blood pressure and hypertension in a day. A total of 117 participants (34 control subjects and 83 hypertensive patients) underwent echocardiographic measurements at rest, twice a day. Simultaneously, the brachial blood pressure was also measured. LV pressure‐strain loop (PSL) was used to calculate global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). The differences in the GLS and MW indices between the groups were compared, and the correlation of blood pressure changes with the changes in GLS and MW indices were evaluated. Compared to the control group, the hypertensive group showed higher GWI, GCW, and GWW but lower GLS and GWE. Absolute changes in blood pressure, GLS, and MW indices in hypertensive patients were significantly higher than that of the control subjects. Blood pressure changes had significant univariate correlation with changes in GLS and MW indices. In conclusion, significant fluctuations in blood pressure could induce changes in MW indices to preserve left ventricular systolic function. Repeated assessment of MW indices is necessary for hypertensive patients with large blood pressure fluctuations.

the left ventricular ejection fraction (LVEF) in predicting cardiovascular mortality. [2][3][4] Furthermore, GLS is associated with left ventricular structural remodeling in patients with hypertension. 5 Hence, GLS has been regarded as a reliable, sensitive, and reproducible tool for evaluating the left ventricular systolic function. 6 It is well known that due to the interaction of different mechanisms in response to external and internal stimuli, blood pressure shows spontaneous fluctuation within 24 hours. 7 These oscillations are documented as a physiological phenomenon, especially in patients with hypertension. 8,9 However, one of the main limitations of GLS is load dependence, which may affect the accuracy of diagnosis. 10 It is challenging to distinguish the actual myocardial dysfunction from cardiac functional changes associated with altered load states in hypertensive patients with high blood pressure variability (BPV).
The concept of "Myocardial work" was once put forward by Suga in 1979. 11 However, due to its invasiveness and complexity, it was not applied widely in clinical practice. Yet, recent studies have confirmed a good correlation and consistency between the invasive and noninvasive left ventricular pressure-strain loop (LV-PSL). 12,13 With the replacement of noninvasive LV-PSL, applying myocardial work (MW) in daily practice has become more feasible. MW is considered as an advancement of GLS, which combines deformation as well as afterload. MW measures the amount of work performed starting from the closure of the mitral valve till its opening, which is an indirect measurement of myocardial metabolism, systolic stroke work, and oxygen consumption. 12 The Normal Reference Ranges for Echocardiography (NORRE) study by Manganaro and associates provides normal reference limits for MW indices. 14 As a part of their study, Manganaro and associates also found that MW indices showed no strong correlation with age and sex. 14 Currently, MW has been used to evaluate left ventricular systolic function under different clinical conditions. In a series of studies, Galli and associates demonstrated that MW may be used as a reliable predictor of response to cardiac resynchronization therapy. [15][16][17] Also, few other studies have shown that MW diagnoses not only hemodynamically significant coronary stenosis in stable coronary arteries but also identifies acute coronary occlusion in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). 18,19 Moreover, the evaluation of MW for other cardiovascular diseases is also going on in full swing. However, to our knowledge, no research has explored the differences in MW indices under different blood pressure conditions in resting state. Hence, the purpose of this article was to investigate the effect of blood pressure changes on MW indices in participants with normal blood pressure and hypertension in a day.

Study cohort
This was a single-center, prospective study that recruited hyperten-

Acquisition of echocardiographic and blood pressure data
Transthoracic echocardiographic imaging was obtained using a Vivid Simultaneous with echocardiography, blood pressure values were measured on the right brachial artery using an automated blood pressure monitor (Omron 7200, Omron Healthcare). Smoking and drinking coffee, tea, or alcohol and exercise were prohibited for 30 minutes before measuring BP. Patients did not fast for lunch but were asked to eat a light and not a full meal. Before the procedure, patients were asked to empty their bladder and relax for 3-5 minutes. During the BP measurements, the patients remained quiet and were in the supine position. The BP measurements were taken thrice with 1-2 minute intervals, and the average value was used for the analyses. 20 Mean arterial blood pressure (MBP) was calculated as one-third of the systolic blood pressure (SBP) plus two-third of the diastolic blood pressure (DBP). Further, SBP was compared in the morning and afternoon and the smaller value was selected as the baseline.

Two-dimensional STE
To evaluate the GLS using STE, the standard imaging windows were acquired from the three apical views (the apical four-chamber, twochamber, and long axis) at frame rates between 50 and 80 frames/s. The myocardial motion in the region of interest was automatically tracked using the Automated Function Imaging software (EchoPAC Version 203). If necessary, the region of interest was adjusted by correcting the edge or width of the endocardium. According to the standardized 17segment heart model, 22 GLS was calculated from the mean of the longitudinal peak systolic strain of all the LV segments. Also, all GLS values were reported using absolute values.

Quantification and analysis of myocardial work
MW was quantified by the noninvasive PSL, which integrated the brachial blood pressure into the LV strain parameters using the Global wasted myocardial work (GWW, mmHg%): the "negative" work performed by the LV segments not contributing to the LV ejection (lengthening during systole and shortening during isovolumic relaxation).
Global myocardial work efficiency (GWE, %): the percentage of myocardial work, calculated as the ratio of GCW to the sum of GCW and GWW.

Intra-and inter-observer variability
Two experienced sonographers re-measured 30 randomly selected participants to assess the repeatability. In the process, sonographers were blinded to the clinical data as well as to each other's results. A month later, the images were analyzed again by the same sonographer to assess the intra-observer variability. The same images were also analyzed by both sonographers to assess the inter-observer variability.

Statistical analysis
All data were collected, statistically analyzed, and tabulated using the were used to assess the inter-and intra-observer variability.

Demographic data
The study cohort included 34 control subjects with no history of hyper-

GLS and MW analysis
The GWI, GCW, and GWW were found to be higher in the hypertensive groups, while GLS and GWE were found to be lower compared to the control group (all P < .05). Among hypertensive patients, GWI, GCW, and GWW were higher in Grade 2 group than that in the Grade 1 group. However, GLS and GWE did not reach significant differences within the hypertensive groups. With the adjustments applied to age, BSA, and BMI at the baseline, no obvious difference was observed in GLS between hypertensive patients and the controls. All information is presented in Tables 2 and 3.
Among hypertensive groups, the values of GWI, GCW, and GWW were higher in the patients with higher SBP state than those in the baseline SBP, while the values of GLS and GWE were lower than those of the baseline SBP (all P < .05). Among controls, only GCW was greater in a higher SBP state compared to the baseline SBP ( Table 2).
The absolute changes in the LV afterload-associated variables (SBP, DBP, MBP), GLS, and MW indices in hypertensive groups were significantly higher than those of the control group. However, no significant differences were observed in the changes of GLS and MW indices within the hypertensive groups (Table 2). When adjusted for age, BSA, and BMI, the absolute changes in the GLS and MW indices were significantly higher in the Grade 2 group than those found in the control group. However, in the Grade 1 group, only the changes in GWW and GWE were greater compared to the control group.
( Table 3).     Figure 2). In the control group, the changes in LV afterload-associated variables did not show a significant relationship with changes in MW indices and GLS.

Evaluation of intra-and inter-observer variabilities
Excellent intra-observer and inter-observer variabilities were observed while measuring the MW parameters (Table 5, Figure 3). For the intra-observer variability, the interclass correlations coefficients (ICC) of GWI, GCW, GWW, and GWE were found to be 0.992, 0.996, 0.991, and 0.986, respectively. For the inter-observer variability, the ICC of GWI, GCW, GWW, and GWE were found to be 0.990, 0.991, 0.980, and 0.968, respectively.

DISCUSSION
Our study described the response of MW indices and GLS to the altered blood pressure in hypertensive patients and healthy control subjects. The main findings of this study were as follows: Firstly, in hypertensive patients, a decrease was observed in the GLS while an increase was seen in the GWI with rising blood pressure with no significant changes observed in the controls. Secondly, compared to the controls with smaller LV afterload changes, the absolute changes in GLS and MW indices in hypertensive patients with higher LV afterload changes were higher. Thirdly, a significant correlation was found between the changes in the LV afterload associated variables (SBP,

DBP, MBP) and changes in the GLS and MW indices.
Evaluating cardiac systolic function has always been a crucial task in the clinical practice of cardiology. GLS reflects the subendocardial function, which is susceptible to wall stress, ischemia, and fibrosis, through the speckle-tracking algorithm. 23 However, numerous studies have confirmed that the increase in afterload was related to the decrease in GLS. 19,24,25 MW is considered as an advancement of GLS by combining deformation as well as the afterload. Compared to GLS and LVEF, MW can reflect additional cardiac performances in the early stages of the disease. Many studies have confirmed excellent intraobserver and inter-observer repeatability of MW indices and results from these studies are also similar to our study. 13,14,24 The GWI, GCW, GWW, and GWE values were obtained based on the MW analysis. The GWI was referred to the total LV work within the area of the PSL, which was found to have a strong correlation with myocardial glucose metabolism. 12 The GCW was referred to as the work that contributed to the LV ejection during systole, whereas GWW focused on quantifying lost energy due to the uncoordinated left ventricular contractions. In the recent studies by Galli and associates, GWW and GCW were shown to predict the response of cardiac asynchrony patients to cardiac resynchronization therapy. [15][16][17] The GWE reflects the efficiency of the mechanical energy consumption during the cardiac cycle.
El Mahdiui and associates demonstrated that GWE was found to be similar in normal individuals and also in the ones with the CV risk factors, but in the post-infarct patients without heart failure and heart failure patients with reduced ejection fraction (HFrEF), it was found to be decreased. 26 Generally, MW provided more information for a better understanding of the relationship between left ventricular deformation and afterload conditions, which could help us to distinguish the myocardial dysfunction happening from the changes associated with altered afterload.
The left ventricular MW indices have been used for the assessment of patients with hypertension. Chan and associates found that the patients with Grade 2 hypertension showed significantly higher GWI and GCW, while in patients with Grade 1 hypertension, these parameters only tended to increase compared to the controls. 24 In another study by Jaglan and associates, which used the 2017 American College of Cardiology guidelines, it was proved that GWI was significantly F I G U R E 1 Variation of myocardial work indices and GLS in two participants with two divergent LV afterload at rest. P1, a subject from the control group; P2, a subject from the hypertensive group. P1: 17-segment bull's-eye illustrated homogenous myocardial work indices and GLS across all segments at two divergent LV afterloads (A1, BP 128/69 mmHg; A2, BP 122/65 mmHg). P2: Compared to B1, the area of the red segment of bull's-eye was found to be reduced while the corresponding GLS and GWE were shown to be improved in the B2 (B1, BP 172/92 mmHg; B2, BP 135/80 mmHg) elevated in both Stage 1 and Stage 2 hypertension. 27 Furthermore, Lembo and associates demonstrated that elevated DBP could not only cause an increase in GWW but also could induce a decrease in GWE. 28 The results of these studies were consistent with our findings. In our study, we found that compared to the control group, the hypertensive group had higher GWI, GCW, and GWW but lower GLS and GWE. We pressure. 29 Secondly, due to the increased afterload, a short-term decline in the LV stroke volume may be observed, which could be compensated by increasing GWI while transferring the LV pumps to a higher energy level. 24,29 However, in controls, no significant changes were observed in the GLS and GWI with elevated afterload. In other words, in the healthy population, GLS and GWI were Additionally, we found that GCW became significantly greater with an increase in SBP. In normal subjects, an augmentation of GCW was not observed along with changes in GWW and GWE, which indicated that the fluctuations of afterload in the physiological range led to an absolute increase in GCW but no changes in GWW and GWE. However, in people with hypertension, substantial augmentations of blood pressure not only increased the effective work but also caused an increment in the GWW. The increase in GWW may be related to the uncoordinated contractions caused by increasing wall stress. Since the increasing GCW could only partially offset GWW, a significant decline was observed in the GWE within the normal range. 14 This finding reminds us that a larger increment in the afterload might diminish the efficacy of myocardial mechanics.
Compared to the controls, the changes in MW indices were higher in hypertensive patients. The possible reason for this may be significantly higher fluctuation of blood pressure in hypertensive patients than those of the controls. Along this line, we found that the changes in SBP, DBP, and MBP showed significant but weak correlations with the changes in MW indices. Elevated blood pressure can be balanced by the myocardial self-regulation mechanism (Frank-Starling mechanism, Anrep effect, and so on), but it may also increase the stiffness and the oxygen consumption of the myocardium. In the long run, chronically raised blood pressure may eventually promote myocardial fibrosis and LV remodeling, further causing LV failure. In hypertensive patients, instantly assessing the left ventricular function parameters may not be a sound clinical evaluation, and repeated observations of GLS and MW indices might be necessary.

Limitations
This study had several limitations. Firstly, it was single-center research with a relatively small sample size. Secondly, although the pre-existing left ventricular pathological changes such as hypertrophy, abnormal contraction, and dilatation may disturb the effect of changes in afterload, we could not perform a more detailed subgroup analysis since it was difficult with the limited sample size. In the subsequent work, we plan to confirm our results in a multicenter study with large sample size.

CONCLUSIONS
In healthy people without structural heart disease or cardiovascular risk factors, MW is relatively insusceptible to oscillations within the physiological range of blood pressure. However, in a population of hypertensive patients, a significant increment in blood pressure may lead to an increase in GWI and GCW to preserve left ventricular systolic function. Additionally, the increased GWW cannot be balanced by GCW, which results in a significant reduction of GWE. Repeated assessments of GLS and MW indices are necessary for hypertensive patients who display high fluctuations in blood pressure.