Left atrial strain predicts cardiovascular response to exercise in young adults with suboptimal blood pressure

To investigate the left ventricular response to exercise in young adults with hypertension, and identify whether this response can be predicted from changes in left atrial function at rest.


INTRODUCTION
The prevalence of hypertension in young adults is increasing, with at least one in 17 adults below the age of 40 years being hypertensive. 1 Blood pressure levels in young adulthood are associated with risk of stroke and cardiovascular disease in later life. 2,3 Therefore, identification of those who may benefit from intervention early in life is important. Traditional biomarkers used to risk stratify patients for treatment, such as left ventricular hypertrophy, tend to be less sensitive for identification of those at risk at younger ages, due to relatively shorter durations of exposure. 4,5 Left ventricular hypertrophy develops because blood pressure elevation increases afterload and left ventricular wall stress. However, gross changes in left ventricular morphology sufficient to reach criteria for the diagnosis of left ventricular hypertrophy are not often observed until severe disease is established. [6][7][8] One of the other reported functional impacts of increased left ventricular loading and myocardial fibrosis [9][10][11] is an abnormal left ventricular response to physical exercise. [12][13][14] This has been observed in older patients with hypertension and, although initially believed to be due to coexisting coronary artery disease, 15 was found in older asymptomatic, moderately-hypertensive patients without evidence of coronary disease. 14 Using speckle tracking echocardiography, changes in left atrial function have also been shown to be altered in older hypertensive patients before the presence of ventricular structural abnormalities. 16 Subclinical alterations of left ventricular mechanics could, in part, be explained by these changes in left atrial function 16,17 as the left atrial booster pump phase, in particular, is known to vary with left ventricular compliance and end diastolic pressure. 18 We hypothesized abnormal left ventricular-atrial coupling should become evident early in the development of hypertension and, therefore, identifiable in young adults with advancing hypertensive disease. 19 To test this hypothesis, we studied whether a reduced left ventricular response to exercise is evident in young people with mild degrees of hypertension. In addition, to examine whether this exercise response could be detected at rest, we tested whether this response can be predicted by changes in left atrial function.

Study population
We performed a retrospective, observational case control study, with frequency matching between groups for age, sex, and bodyweight.

Cardiopulmonary exercise test (CPET)
A peak Cardiopulmonary exercise test (CPET) was completed for all participants following a validated protocol on a seated stationary cycle ergometer (Ergoline GmbH, Bitz, Germany) with instructions to maintain a rate of 60 rotations per minutes throughout the test.
Ventilation variables and respiratory gases were recorded using a computer-based system (Metalyzer 3B, Cortex Biophysik, Leipzig, Germany). Perceived exertion rate was collected every 2 minutes using the standard Borg scale. Every 3 minutes, a blood pressure measurement was taken by a manual mercury sphygmomanometer (Accoson Freestyle, Essex, United Kingdom). The test was continuously monitored by a trained investigator, and prior to the procedure participants were encouraged to reach their maximum exercise intensity.

Stress echocardiography
Echocardiography imaging was obtained on the upright cycle position during a moderate exercise intensity for all participants. Moderate exercise intensity was identified by performing a CPET prior to the stress echocardiography imaging for the first 56 participants. For the remainder, a simplified protocol was used comprising of a single CPET with optimal timing of echocardiography planned before the procedure based on calculation of an exercise heart rate zone coinciding with an estimated 60% of heart rate reserve. 25

Statistical analysis
To determine blood pressure-related differences, either systolic and/or diastolic blood pressure ≥120/80mm Hg were classified in the suboptimal blood pressure group and compared to an age, sex, and frequencymatched optimal blood pressure group (<120/80 mm Hg). Statistical analyses were performed using R software Version (4.0.2). Shapiro-Wilk test and visual assessment were used to assess for normality.
Between-group comparisons were performed using independent samples Student t-tests for normally distributed data and Mann-Whitney participants in each group, allowed a 5% difference in ejection fraction to be identified between groups with 85% power at α = .05. As this was a retrospective study, we included all participants who met the inclusion criteria, which was greater than 100 participants.

Baseline clinical characteristics
We identified 127 young adults (59 with optimal blood pressure and 68 with suboptimal blood pressure) who fulfilled the selection criteria and had images available for analysis. Resting brachial systolic and diastolic clinic blood pressure in the suboptimal blood pressure group were 130 ± 9 mm Hg and 79 ± 9 mm Hg and in the optimal blood pressure group 113 ± 9 mm Hg and 67 ± 6 mm Hg. The daily physical activity levels were similar in both groups. Group baseline clinical characteristics are provided in Table 1.

Resting echocardiography
Echocardiography results at rest are presented in Table 2

3.3
Physical exercise blood pressure, echocardiography, and fitness Table 3  were also similar between groups. There was no association between daily physical activity and exercise left ventricular ejection fraction (p = 0.542) even when adjusted for age, sex, and body mass index (p = 0.722).

Prediction of cardiac response to physical exercise
Association between resting echocardiography parameters and left ventricular response to physical exercise adjusted for age, sex, body mass index, and mean arterial blood pressure is presented in Table 4.    Figure 2 demonstrates the association between exercise ejection fraction and resting left atrial pump function. In those with suboptimal blood pressure, the sensitivity and specificity for identification of those likely to have lower ejection fraction value during exercise (≤75%) when left atrial contraction strain is measured equal to or below 9% was calculated at 64.5% and 71.4%, respectively.

DISCUSSION
In this study, we investigated the differences in left ventricular response to physical exercise between young adults with optimal and suboptimal blood pressure, and whether this response is associated with subclinical resting left atrial remodelling. Young adults with suboptimal blood pressure (≥120/80 mm Hg) had lower left ventricular ejection fraction during moderate exercise intensity when compared to those with optimal blood pressure (<120/80 mm Hg  to the atrioventricular pressure gradient, rather than intrinsic left atrial myocardial function. 32

STUDY LIMITATIONS
Firstly, our study is a case-control study using retrospective data to understand pathophysiological mechanisms. Although participant selection was not dependent on the echocardiographic parameters, repeated studies in clinical populations are required to replicate the results. Secondly, a relatively large number of participants were excluded from the analysis because the frame rates required for assessment of left ventricular ejection fraction and global longitudinal strain could not always be acquired due to the increase in heart and breathing rate during moderate exercise. This potentially could bias the study population to those with higher levels of fitness (with relatively lower heart rate and breathing rate during moderate exercise workload), which might lead to an underestimation in differences between groups.
Thirdly, resting echocardiography was performed in the lateral decubitus position, while the exercise images were obtained on the upright cycle position. The upright cycle ergometry was selected for CPET and stress echocardiography to minimize torso movement during image acquisition. However, this means we cannot directly compare ejection fraction at baseline with those acquired during moderate exercise due to the effect of change in posture. 36 Finally, left atrial strain assessment was performed at rest only using left ventricular speckle tracking software due to lack of validated specific left atrial speckle tracking software. However, for the left atrial assessment endocardial tracking was selected, and the QRS complex was used as a reference point, following the latest EACVI recommendations for left atrial strain measurements. 24 Left atrial assessment during exercise was not considered as the aim of this work was to predict left ventricular response during exercise from resting echocardiography parameters. Therefore, echocardiography imaging during exercise was focused on the left ventricle. This ensured optimal left ventricular image quality during exercise.

CONCLUSION
This study shows that young adults with suboptimal blood pressure have physiological differences in their submaximal left ventricular ejection fraction response to physical exercise. This response was independently associated with left atrial booster pump function at rest.
Subclinical left atrial remodelling appears to be an independent early marker of cardiac alterations secondary to elevated blood pressure in young adults.