High-normal blood pressure, functional capacity and left heart mechanics: Is there any connection?

Abstract

Objective. To evaluate the relationship between functional capacity and left ventricular (LV) and left atrial (LA) myocardial deformation, assessed by two- and three-dimensional (2DE and 3DE) strain analysis, in subjects with high-normal blood pressure (BP). Methods. This cross-sectional study included 64 subjects with optimal BP and 75 subjects with high-normal BP of similar gender and age. All the subjects underwent a complete 2DE and 3DE examination and cardiopulmonary exercise testing. Results. 3DE global longitudinal strain was significantly lower in the group with high-normal BP than in the optimal BP group (− 20.1 ± 2.4 vs − 18.5 ± 2.3%, p < 0.001). Similar results were obtained for 3DE global circumferential strain (− 21.8 ± 2.6 vs − 19.3 ± 2.4%, p < 0.001), as well as for 3DE global radial strain (45.1 ± 8.8 vs 42.3 ± 7.2%, p = 0.042), and 3DE global area strain (− 30.1 ± 4.2 vs − 28.1 ± 3.8%, p < 0.001). LV twist was similar between the observed groups, whereas untwisting rate was significantly decreased in the subjects with high-normal BP (− 123 ± 30 vs − 112 ± 26°/s, p = 0.023). Peak VO2 was significantly lower in the high-normal BP group (30.8 ± 4 vs 28.3 ± 3.7 ml/kg/min, p < 0.001). 2DE LV ejection fraction (β = 0.38, p = 0.014), 2DE global longitudinal strain (β = 0.35, p = 0.019) and 3DE global longitudinal strain (β = 0.27, p = 0.042) were independently associated with peak VO2. Conclusion. LV and LA mechanics, as well as functional capacity are significantly impaired in the subjects with high-normal BP. LV and LA myocardial deformations are associated with peak oxygen uptake.

Key Words::

• Functional capacity
• high-normal blood pressure
• left ventricle
• left atrium
• speckle tracking echocardiography

Introduction

According to the European guidelines for arterial hypertension, high-normal blood pressure (BP) was defined as systolic BP between 130 and 139 mmHg and/or diastolic BP between 85 and 89 mmHg (1), whereas JNC 7 established the term prehypertension for systolic BP between 120 and 139 mmHg and/or diastolic BP between 80 and 89 mmHg (2). Despite the differences in cut-off values, studies showed that these entities are associated with a higher risk of developing hypertension and an increased incidence of cardiovascular disease (3). A recently published meta-analysis revealed that high-normal BP is associated with cardiovascular events and mortality, but not with all-cause mortality (4), which was also confirmed by Guo et al. (5).

The influence of high-normal BP on left ventricular (LV) structure and function has not been fully understood. Although LV structure and diastolic function are impaired in high-normal BP (6,7), studies revealed that high-normal BP was not an independent predictor of target organ damage (6), neither that LV diastolic function was an independent predictor of progression from high-normal BP to hypertension (8). The impact of high-normal BP on LV mechanics has been poorly investigated. Di Bello et al. (9) were the first who showed that longitudinal LV function was impaired in the high-normal BP subjects.

Kokkinos et al. (10) demonstrated that exercise capacity is an independent predictor of overall mortality in high-normal BP subjects (10), and that moderate intensity of physical activity can improve hemodynamics in these individuals and reduce the work of the LV, which results in decreased LV mass (11). To our knowledge, there is no study that investigated LV and left atrial (LA) myocardial mechanics by using two- and three-dimensional (2DE and 3DE) speckle tracking imaging and correlated these parameters with functional capacity in subjects with high-normal BP.

The purpose of our research was to determine functional capacity, as well as LV and LA mechanics by 2DE and 3DE strain analysis in the patients with high-normal BP, and to investigate the relation between LV and LA myocardial deformation and functional capacity.

Methodology

Between November 2011 and May 2013, we enrolled 139 subjects who were referred to our outpatient clinic as a part of the screening program for primary prevention of cardiovascular diseases. Exclusion criteria were age > 60, arterial hypertension, antihypertensive treatment, heart failure, coronary artery disease, previous cerebrovascular events, atrial fibrillation, congenital heart disease, valvular heart disease, obesity (BMI ≥ 30 kg/m²), neoplastic disease, cirrhosis of the liver, kidney failure or endocrinological diseases including type 2 diabetes mellitus. Subjects with unsatisfactory 3DE acquisitions (six participants) were also excluded from any further analyses.

Clinic BP values were obtained in two separate visits 3 weeks apart. BP was measured by conventional sphygmomanometer in the morning hours by taking the average value of three consecutive measurements in the sitting position 10 min apart. BP was calculated as average values between all measurements. High-normal BP was defined according to the current guidelines (1): systolic BP between 120 and 130 mmHg and diastolic BP between 85 and 90 mmHg.

Anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, total cholesterol and triglycerides) were obtained from all the subjects included in the study. Body mass index (BMI) and body surface area (BSA) were calculated for each patient. The study was approved by the local ethics committee, and informed consent was obtained from all the participants.

Echocardiography

Echocardiographic examinations were performed by using a commercially available Vivid 7 (GE Vingmed, Horten, Norway) ultrasound machine equipped with both a 2.5-MHz transducer and a 3-V matrix probe for 3DE data set acquisitions.

Reported values of all 2DE parameters were obtained as the average value of three consecutive cardiac cycles. LV diameters, posterior wall and septum thickness were measured according to the current recommendations (12). Relative wall thickness was calculated according to the relevant formula. LV ejection fraction (EF) was calculated using the biplane method. LV mass was calculated by using the Devereux formula (13), and indexed for the height powered to 2.7.

Pulsed-wave Doppler assessment of transmitral LV was obtained in the apical four-chamber view according to the guidelines (14). Tissue Doppler imaging was used to obtain LV myocardial velocities in the apical four-chamber view, with a sample volume placed at the septal and lateral segments of the mitral annulus during early and late diastole (e' and a'), and systole (s). The average of the peak early diastolic relaxation velocity (e') of the septal and lateral mitral annulus was calculated, and the E/e' ratio was computed.

LA volumes were determined according to the biplane area-length method in four- and two-chamber views, and all the values were indexed for BSA. LA total emptying fraction was calculated from LA volumes.

2DE strain and strain rate

2DE strain analysis was performed by using three apical (long-axis, four- and two-chamber) views and three parasternal short-axis views of the LV (basal, just below the mitral level; mid-ventricle, at the papillary muscle level; and apical) (15). Commercially available software (EchoPAC 110.1.2, GE-Healthcare, Horten, Norway) was used for 2DE strain quantitation.

2DE longitudinal strain was calculated by averaging all the values of regional peak longitudinal strain values obtained in three apical views. 2DE circumferential and radial strain and strain rate were assessed as the average of the LV six regional values measured in the parasternal short-axis view, at the level of papillary muscles. To evaluate LV twist, six tracking points were placed on end- diastolic frame short-axis views obtained at basal and apical LV levels (15). LV twist values and untwisting rate were calculated by software. LV torsion was calculated when LV twist was divided by end-diastolic LV length.

The LA speckle tracking analysis was done in the four- and two-chamber views (15). The LA endocardium was manually traced in order to evaluate the LA myocardial deformation. LA peak longitudinal strain was calculated by averaging the values obtained in four- and two-chamber apical views.

3DE examination

A full-volume acquisition of the LV was obtained by harmonic imaging from the apical approach. Six ECG-gated consecutive beats were acquired during end-expiratory breath-hold to generate LV full volume. Depth and volume size were adjusted to obtain a temporal resolution higher than 30 volumes/s. All data sets were analyzed offline using commercially available software (4D Auto LVQ, GE-Vingmed, Horten, Norway). The 3DE global deformation parameters: longitudinal, circumferential, radial and area strain were calculated as weighted averages of the regional values from the 17 myocardial segments at end-systole (16). If three or more segments were rejected, global strain values were not calculated, and these patients were excluded from any further analyses.

Cardiopulmonary exercise testing

All the study participants underwent a maximum symptom-limited treadmill exercise test according to a modified Bruce ramp protocol (adding to the standard Bruce protocol stage 3 min; 1.7 km/h, at 5% grading). Patients were encouraged to continue with the test for as long as their respiratory exchange ratio exceeded 1. The peak oxygen uptake (peak VO2) was assessed by breath-by-breath gas analysis (Schiller, CARDIOVIT CS-200 Ergospiro system). Peak VO2 was defined as an average value within the last 20 s of exercise and expressed as ml/kg/min. BP and heart rate were measured before, during the exercise test and during recovery period. BP assessments were performed on the non-dominant arm.

Statistical analysis

Continuous variables were presented as mean± standard deviation (SD), and the Student t-test was used to detect differences between the two groups, as they showed normal distribution. Differences in proportions were compared by using the χ². Pearson's correlation coefficient was used for determining the correlation between different 2DE and 3DE parameters and VO2max. The variables which showed p-value ≤ 0.10 were included into the stepwise multiple regression analyses. Inter- and intra-observer variability was examined by using Pearson's bivariate two-tailed correlations. The p < 0.05 was considered statistically significant.

Results

In our study, there was no difference in age, BSA and sex distribution between the two observed groups (Table I). Additionally, the levels of fasting glucose, total cholesterol and triglycerides were similar among the groups. Systolic and diastolic BP values were significantly higher in the subjects with high-normal BP (Table I).

Table I. Demographic characteristics and clinical parameters of study population.

	Optimal BP (n = 64)	High-normal BP (n = 75)	p
Age (years)	46 ± 9	48 ± 9	0.194
Female (%)	27 (42)	30 (40)	0.863
BMI (kg/m^2)	23.6 ± 2.5	24.3 ± 2.7	0.117
BSA (m^2)	1.89 ± 0.21	1.95 ± 0.23	0.113
Clinic SBP (mmHg)	120 ± 7	134 ± 4	< 0.001
Clinic DBP (mmHg)	72 ± 6	84 ± 4	< 0.001
Plasma glucose (mmol/l)	5.1 ± 0.4	5.2 ± 0.5	0.2
Triglycerides (mmol/l)	1.66 ± 0.24	1.59 ± 0.26	0.104
Total cholesterol (mmol/l)	4.97 ± 0.58	5.06 ± 0.55	0.35

BP, blood pressure; BMI, body mass index; BSA, body surface area; SBP, systolic blood pressure; DBP, diastolic blood pressure.

There was no difference in LV diameters and LV EF between the observed groups, whereas LV interventricular septum thickness and relative wall thickness, as well as LV mass index, were increased in the high-normal BP group (Table II). The LA diameter and volumes were increased, whereas LA EF was decreased (56 ± 6 vs 52 ± 5%, p < 0.001) in the subjects with high-normal BP. LV diastolic function estimated by E/A, e'/a' and E/e' ratios and mitral deceleration time was significantly deteriorated in the group of subjects with high-normal BP (Table II).

Table II. Echocardiographic parameters of study population.

	Optimal BP (n = 64)	High-normal BP (n = 75)	p
Two-dimensional echocardiographic parameters
LVEDD (mm)	48 ± 4.5	49.2 ± 4.9	0.138
LVESD (mm)	32 ± 3.8	33 ± 4	0.135
IVS (mm)	9 ± 1.1	10 ± 1	< 0.001
RWT	0.33 ± 0.04	0.38 ± 0.05	< 0.001
LA (mm)	35.1 ± 3.1	37.2 ± 3.6	< 0.001
LVM/Ht^2.7 (g/m^2.7)	38.4 ± 5.2	44.8 ± 6.5	< 0.001
EF (%)	65 ± 5	64 ± 5	0.242
LA max volume index (ml/m^2)	28.4 ± 5.5	30.9 ± 6.6	0.018
LA min volume index (ml/m^2)	12.6 ± 7.3	14.9 ± 8.3	0.088
LA EF (%)	56 ± 6	52 ± 5	< 0.001
E/A ratio	1.28 ± 0.26	1.19 ± 0.24	0.035
DT (ms)	185 ± 27	202 ± 29	< 0.001
e'/a'	1.17 ± 0.2	1.08 ± 0.26	0.026
E/e' ratio	5.7 ± 1.9	6.8 ± 2.1	0.002
s (cm/s)	8.2 ± 2	7.8 ± 1.8	0.217
Two-dimensional LV and LA speckle tracking analysis
Peak LV systolic strain (%)
Global longitudinal strain	− 21.9 ± 2.4	− 19.7 ± 2	< 0.001
Global circumferential strain	− 23.4 ± 3.2	− 21.5 ± 3.1	< 0.001
Global radial strain	49.6 ± 13.6	47.1 ± 13	0.26
LV torsion (°/cm)	1.6 ± 0.5	1.5 ± 0.4	0.191
LV untwisting rate (°/s)	− 123 ± 30	− 112 ± 26	0.023
LA global longitudinal strain (%)	38.6 ± 6.7	35.2 ± 6	0.002
Three-dimensional speckle tracking analysis
Global longitudinal strain (%)	− 20.1 ± 2.4	− 18.5 ± 2.3	< 0.001
Global circumferential strain (%)	− 21.8 ± 2.6	− 19.3 ± 2.4	< 0.001
Global radial strain (%)	45.1 ± 8.8	42.3 ± 7.2	0.042
Global area strain (%)	− 30.1 ± 4.2	− 28.2 ± 3.8	0.007

BP, blood pressure; LVEDD, left ventricle end-diastolic dimension; LVESD, left ventricle end-systolic dimension; IVS, interventricular septum; RWT, relative wall thickness; LA, left atrium; LVM, left ventricle mass; Ht, height; EF, ejection fraction; DT, deceleration time; A, late diastolic mitral flow (pulse Doppler); E, early diastolic mitral flow (pulse Doppler); e', average of the peak early diastolic relaxation velocity (e') of the septal and lateral mitral annulus (tissue Doppler).

2DE speckle tracking analyses revealed that LV longitudinal (− 21.9 ± 2.4 vs − 20.2 ± 2%, p < 0.001) and circumferential (− 23.4 ± 3.2 vs − 22.1 ± 3.1%, p < 0.001) myocardial functions were impaired in the participants with high-normal BP, whereas LV radial function was preserved. LV torsion was similar between the two groups, while untwisting rate was significantly lower in the subjects with high-normal BP (− 123 ± 30 vs − 112 ± 26°/s, p = 0.023 (Table II). LA global strain was also significantly decreased in this group (38.6 ± 6.7 vs 35.2 ± 6%, p = 0.002) (Table II).

3DE LV deformation was also significantly impaired in the high-normal BP group in all three directions (Table II). Thus, longitudinal (− 20.1 ± 2.4 vs − 18.5 ± 2.3%, p < 0.001), circumferential (− 21.8 ± 2.6 vs − 19.3 ± 2.4%, p < 001) and radial (45.1 ± 8.8 vs 42.3 ± 7.2%, p = 0.042.) strains were significantly lower in these subjects, as well as area strain (− 30.1 ± 4.2 vs − 28.2 ± 3.8%, p = 0.007) (Table II).

Heart rates before cardiopulmonary exercise testing and at the peak of the test were similar among the two groups, whereas systolic and diastolic BP were significantly higher in the group with high- normal BP (Table III). At the peak of testing, systolic BP (167 ± 16 vs 183 ± 19 mmHg, p < 0.001) and diastolic BP (92 ± 5 vs 100 ± 6 mmHg, p < 0.001) were significantly higher in the high-normal BP subjects (Table III). Respiratory exchange ratio was similar between the two groups, whereas maximal load (5.8 ± 1.1 vs 5.4 ± 1 km/h, p = 0.026) and peak VO2 (30.8 ± 4 vs 28.3 ± 3.7 ml/kg/min, p < 0.001) were significantly lower in the high-normal BP group (Table III).

Table III. Cardiopulmonary exercise testing parameters of study population.

	Optimal BP (n = 64)	High-normal BP (n = 75)	P
Heart rate (beat/min)	70 ± 7	71 ± 8	0.438
SBP before testing (mmHg)	118 ± 6	133 ± 5	< 0.001
DBP before testing (mmHg)	71 ± 6	83 ± 4	< 0.001
Maximal heart rate (beat/min)	168 ± 12	170 ± 13	0.353
SBP max (mmHg)	167 ± 16	183 ± 19	< 0.001
DBP max (mmHg)	92 ± 5	100 ± 6	< 0.001
Maximal load (km/h)	5.8 ± 1.1	5.4 ± 1	0.026
Respiratory exchange ratio	1.09 ± 0.7	1.07 ± 0.6	0.86
Peak VO2 (ml/kg/min)	30.8 ± 4	28.3 ± 3.7	< 0.001

BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; VO2, oxygen consumption.

The analysis revealed that systolic BP (r = − 0.23, p = 0.047), 2DE LV EF (r = 0.41, p = 0.002), 2DE LV global longitudinal strain (r = 0.42, p = 0.001), 2DE LV global circumferential strain (r = 0.27, p = 0.032), 2DE LA global strain (r = 0.33, p = 0.02), 3DE LV global longitudinal strain (r = 0.36, p = 0.013) and global area strain (r = 0.26, p = 0.039) correlated with peak VO2 in the whole study population. However, only 2DE LV EF (β = 0.36, p = 0.015), 3DE global longitudinal strain (β = 0.28, p = 0.035) and 2DE LA strain (β = 0.22, p = 0.046) were independently associated with peak VO2.

Interobserver variability

Pearson's correlations: 3DE global longitudinal strain: r = 0.89, p < 0.001; 3DE global circumferential strain: 0.78, p < 0.001; 3DE global radial strain: r = 0.62, p = 0.001; 3DE global area strain: r = 0.85, p < 0.001.

Intraobserver variability

Pearson's correlations: 3DE global longitudinal strain: r = 0.93, p < 0.001; 3DE global circumferential strain: 0.84, p < 0.001; 3DE global radial strain: r = 0.73, p < 0.001; 3DE global area strain: r = 0.89, p < 0.001.

Discussion

Our study revealed several new findings: (i) LV myocardial deformation is impaired in the subjects with high-normal BP; (ii) LA mechanics is also deteriorated in the high-normal BP individuals; (iii) functional capacity is decreased in the participants with high-normal BP; and (iv) LV and LA mechanics are associated with functional capacity independently of LV systolic function.

The present study revealed that LV myocardial deformation is impaired in all three directions (longitudinal, circumferential and radial) in the high-normal BP participants. Previously Di Bello et al. (9) found similar results for the longitudinal LV function in the same population. Galderisi et al. (17) investigated young hypertensive patients with mild hypertension and normal LV mass and revealed deterioration of LV myocardial deformation in all three directions, which is in line with our findings. The authors also found a significant correlation between 3DE LV deformation and LV mass index, as well as the BP level (17). These results could partly explain the impairment of LV deformation in high-normal subjects because our results also demonstrated that LV mass index was increased in these subjects, even though it still remained in the normal range.

The deterioration of LV mechanics in all three directions is very important because LV longitudinal and circumferential functions are significantly related with LV systolic function (18). Moreover, it has been recently shown that LV longitudinal myocardial strain is an independent predictor of all-cause mortality, which increases its clinical significance (19). Our results showed that 3DE LV area strain, the combination of longitudinal and circumferential strain, was reduced in high-normal BP subjects, which indicates mild impairment of global and regional LV function in this population (16,17).

The present study showed furthermore that LV torsion was preserved, whereas LV untwisting rate, the parameter of LV systolic and diastolic function (20), was significantly impaired in the high-normal BP individuals, which additionally confirms impaired LV deformation in these subjects.

Our investigation revealed a significantly impaired LA function and mechanics in the high-normal BP subjects. Other authors also found increased LA volume in the participants with high-normal BP, but they did not investigate LA mechanics (7,21).

Several mechanisms could explain impaired LV and LA mechanical function in the high-normal BP subjects. First, negative association between LV mass and LV deformation could be the reason of LV dysfunction in the high-normal BP group even if LV mass is in the normal range (17). Second, autonomic nervous system disbalance in favor of sympathetic nervous system found in the high-normal BP subjects (22) could be responsible for increased systemic resistance and afterload, which contribute to LV dysfunction. Third, coronary flow reserve in these individuals is lower than in the subjects with optimal BP due to increment of the coronary resistance and presence of LV hypertrophy (23), which could also be responsible for LV mechanical changes in the high-normal BP subjects. Additionally, LA myocardial dysfunction in high-normal BP could be explained by LV pressure overload and LV diastolic dysfunction, similarly to those in hypertension (24).

The results of our research showed decreased functional capacity in the high-normal BP group, which is in line with other similar studies (10,22). This finding is clinically important because Kokkinos et al. (25) have already demonstrated that exercise capacity is associated with all-cause mortality in this population. The relationship between BP and peak oxygen uptake, as well as the underlying mechanisms, is still insufficiently studied. There are studies that link LV systolic and diastolic dysfunction, as well as LV hypertrophy with decreased oxygen uptake (26). These mechanisms could be applied to the subjects with high-normal BP because they have impaired LV diastolic function and higher LV mass comparing with the subjects with optimal BP. Furthermore, there is also a possibility that increased systemic and pulmonary vascular resistance caused by endothelial damage, as well as increased catecholamines or angiotensin II levels, could be responsible for reduced functional capacity in the subjects with high-normal BP.

A significant correlation between LV and LA mechanics with peak oxygen uptake was detected in the whole study population, which represents a new finding. Additionally, only LV myocardial deformation assessed by 2DE and 3DE speckle tracking imaging was associated with functional capacity independently of LV systolic function. Kusunose et al. (27) recently showed the important relationship between LA function and exercise capacity in subjects with preserved LV EF. The authors emphasized the role of ventriculo-atrial coupling to cardiac dysfunction and reduced exercise capacity in the subjects with preserved LV EF. To our knowledge, a similar study, which estimated LV myocardial deformation and functional capacity in high-normal BP subjects, has not been done thus far. Considering our results, the most probable cause of the relationship between functional capacity and LV and LA mechanics is impaired LV systolic and diastolic function in the participants with high-normal BP. Namely, our results demonstrated that 2DE and 3DE LV myocardial deformation is deteriorated in the high- normal BP subjects, which undoubtedly indicates the subtle impairment of LV systolic function; furthermore, all parameters of LV diastolic function are impaired in this group.

Limitations

Our investigations have several limitations. First, 3DE assessment of LV structure and function is significantly influenced by the quality of ultrasound images, especially during the full-volume acquisition. However, the 3DE acquisition feasibility in the present study was very high (95%). Second, a relatively small number of participants in our study might also represent a limitation. Third, the lack of out-of-office BP measurements did not enable us information on the potential impact of masked hypertension on cardiac mechanics and functional capacity. This may have important clinical implications, as it has been shown that individuals with high-normal office BP and/or exaggerated BP response to physical exercise, exhibit a greater likelihood of masked hypertension compared with their counterparts with optimal BP (28).

Conclusion

LV and atrial mechanics obtained by 2DE and 3DE speckle tracking imaging are impaired in population with high-normal BP. Functional capacity is decreased in high-normal BP individuals. LV and LA myocardial deformations are associated with peak oxygen uptake in the whole study population. Further longitudinal analyses with larger number of participants are needed to investigate the impact of mechanical myocardial changes on cardiovascular morbidity and mortality in high-normal BP population.

Potential conflict of interest: None.