Left ventricular function and contractile reserve in patients with hypertension

Left ventricular function and contractile reserve in patients with hypertension Abstract Aims An impaired contractile reserve (CR) may be an early manifestation of left ventricular (LV) systolic dysfunction in hypertensive patients. Using normotensive patients as controls, we examined LV CR and its correlates in hypertensive patients. Methods and results One hundred and twenty-nine (68 men, aged 58.6 ± 9.5 years, 73 had hypertension) patients underwent dobutamine echocardiography. Patients with significant coronary or valvular disease, previous myocardial infarction or revascularization, and diabetes were excluded. LV ejection fraction (LVEF), global longitudinal strain (GLS), circumferential, and radial strain were measured at rest and at low-dose dobutamine. Absolute CR was calculated as the difference in LVEF and multi-directional strain between low-dose dobutamine and their corresponding resting values. Relative CR is the ratio of absolute CR to their corresponding resting values. Hypertensive patients, compared with controls, have significantly impaired GLS at rest (−16.8 ± 2.2% vs. −19.6 ± 1.5%, P < 0.0001) and at low-dose dobutamine (−17.9 ± 2.7% vs. −22.8 ± 2.6%, P < 0.0001). Absolute and relative GLS CR were significantly lower in hypertensive patients (−1.1 ± 2.1% vs. −3.2 ± 2.2% and 7.4 ± 13.9% vs. 16.4 ± 11.7%, respectively, both P < 0.001). Circumferential strain was preserved at rest but impaired at low-dose dobutamine in hypertensive patients (−23.0 ± 4.1% vs. −25.2 ± 3.4%, P = 0.002). There were no differences in LVEF or radial strain between the groups. LV wall thickness and systolic blood pressure correlated significantly with GLS at rest and at low-dose dobutamine. LV wall thickness is the only independent correlates of absolute CR. Conclusion Compared with controls, hypertensive patients have impaired LV GLS at rest and impaired CR despite normal LVEF. Impaired CR correlated with LV wall thickness but independent of prevailing blood pressure. hypertension, ventricular function, contractile reserve, echocardiography, speckle tracking strain Introduction Hypertension is a prevalent and well-recognised cardiovascular risk factor, which may lead to left ventricular (LV) systolic impairment through chronic pressure overload. LV hypertrophy (LVH) is a compensatory process in response to increased wall stress. However, this initially useful adaptive mechanism later becomes ‘a pathological change’ in the myocardium. Whilst LVH has been shown to be a powerful independent predictor for cardiovascular morbidity and mortality,1,2 it can occur late. Multiple recent studies have shown that LV ejection fraction (LVEF) lacks accuracy and sensitivity in detecting early subclinical impairment. In contrast, LV strain analysis has been proven to be more sensitive in detecting early subclinical LV systolic dysfunction, when the LVEF is still within ‘normal’ limits.3–6 LV systolic dysfunction in the early stage can be subtle and subclinical. Resting systolic function may remain preserved, but contractile reserve (CR) to inotropic stimulation may be blunted. A depressed CR has been documented in patients with aortic stenosis,7 mitral regurgitation,8 aortic regurgitation,9 and in diabetic cardiomyopathy,10 and is thought to represent an early manifestation of LV dysfunction. Similarly, impaired CR may be an early manifestation of LV systolic impairment in hypertensive patients. The aim of this study was to examine CR and its correlates in hypertensive patients and examine the relationship between impaired CR and resting LV systolic function as assessed by LV deformation. A group of normotensive patients was recruited as controls. Methods Study population Patients who were referred for invasive coronary angiogram were screened for suitability of recruitment into the study. Patients with significant coronary artery disease, defined as >50% stenosis in any major epicardial coronary arteries or its major branches on coronary angiography, were excluded. Other exclusion criteria included non-sinus rhythm, left bundle branch block, coexisting significant left sided valvular heart disease (more than mild in severity), diabetes mellitus, previous myocardial infarction, or coronary revascularisation. One hundred and thirty-two patients were prospectively recruited into the study. Three patients were subsequently excluded due to poor image quality, 129 patients were included in the final analysis. Seventy three (56%) patients had treated hypertension. This research study was approved by the Human Research Ethics Committee of the South Western Sydney Local Health District, and written informed consent was obtained from all participants. Echocardiography A comprehensive transthoracic echocardiogram with appropriate 2D, colour, and Doppler imaging were performed from standard transthoracic imaging windows using commercially available ultrasound machine Vivid E9 (GE Medical Systems, Horten, Norway). Zoomed LV views were obtained at high frame rates (≥70 frame/s) from the apical four-, two-, and three-chambers, as well as parasternal short-axis views at the papillary muscle level for optimal speckle-tracking strain analysis. All studies were digitally stored and analysed off-line. LV wall thickness and biplane modified Simpson’s LVEF were measured using standard recommendations for LV chamber quantification.11 Dobutamine stress echocardiography Dobutamine stress echocardiography was performed in all participants according to standard protocol. Intravenous dobutamine was infused in incremental doses starting at 5 µg/kg/min. The dose was then increased to 10 µg/kg/min and 20 µg/kg/min at 3 min interval. Standard parasternal long- and short-axis views, and apical four-, two-, and three-chamber views of the left ventricle were obtained at rest and at the end of each infusion stage. Patients who were on β-blockers or non-dihydropyridine calcium blockers had their low-dose echocardiography assessment performed at 20 µg/kg/min; for the remaining patients, the low-dose assessment was performed at 10 µg/kg/min. These doses were chosen as they have been previously demonstrated to be safe and effective in detecting CR, without affecting heart rate, blood pressure (BP), or loading conditions.12,13 Visual wall motion analysis was performed by an experienced investigator using the American Society of Echocardiography’s 16 segment model in a blinded fashion.11 2D multi-directional speckle tracking strain analysis The 2D speckle tracking strain analyses were performed on grey scale images of the left ventricle using Echopac (Version BT13, GE Medical Systems). Peak global systolic longitudinal strain was measured from the 18 segment measurements (six segments from each of the apical four-, two-, and three-chamber views). Peak systolic circumferential and radial strain were measured from the six segments in the parasternal short-axis view of the left ventricle at the papillary muscle level. The Echopac software provided both global and segmental strain values but only the global strain values were included in the analysis. During strain analysis, the endocardial border was manually traced at end-systole, and the width of the region of interest manually adjusted to include the entire myocardial wall thickness. The Echopac software then automatically tracks and accepts segments with good tracking quality and rejects poorly tracked segments. The operator was able to manually override computer-generated tracking and accept or reject individual segments based on visual assessments of the tracking quality. Three cardiac cycles were analysed and the measurements averaged. Normal resting peak global longitudinal strain (GLS) was defined as less than −20% based on previously published literature.11 Assessment of LV CR LVEF and strain analysis were performed both at rest and at low-dose dobutamine. Absolute CR was calculated as the difference in LVEF and multi-directional strain between the low-dose and their corresponding resting values. Relative CR was defined as the ratio of absolute CR to the corresponding resting values, and expressed as percentage. Impaired CR was defined as an absolute CR of ≤5% as measured by LVEF.14 Statistical analysis All continuous variables are reported as the mean ± 1 standard deviation unless otherwise stated. Categorical variables are presented as frequencies and percentages. All continuous variables were evaluated for normality of distribution to ensure the assumptions of subsequent tests were met. Paired student’s t-test was used to compare the results from the baseline and low-dose dobutamine for each subject. The χ2 test was used for evaluation of categorical variables. Linear correlation between strain and echocardiographic measurements were assessed using Pearson correlation coefficients. P-values of ≤0.05 were considered significant. All statistical analyses were performed using SPSS for Windows (IBM SPSS Statistics, version 23). Intra-observer and inter-observer variability analysis Strain analyses were repeated in 10 randomly selected patients at least 4 weeks after the initial analysis by the original investigator and by a second investigator, both blinded to the original measurements, to assess intra-observer and inter-observer variability, respectively. Intra-class correlation (ICC) was evaluated. Results Patient characteristics One hundred twenty-nine patients were included in this study (68 men, aged 58.6 ± 9.5 years), with 73 (56%) patients having treated hypertension. Baseline demographic and clinical characteristics are summarized in Table 1. The normotensive group tended to be younger. There were no statistically significant differences in the gender, body mass index, body surface area, or prevalence of background cardiovascular risk factor profile between the groups, except for hypertension by virtue of the study design. This is also reflected in the differences in the use of antihypertensive medications. Table 1 Demographic and clinical characteristics of the study population Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 P-values comparing hypertensive patients with normotensive controls, by independent sample’s t-tests for continuous variable, and by χ2 test for categorical variables. BMI, body mass index; BSA, body surface area; BP, blood pressure; HR, heart rate; TIA, transient ischaemia attack; IHD, ischaemia heart disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation. Table 1 Demographic and clinical characteristics of the study population Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 P-values comparing hypertensive patients with normotensive controls, by independent sample’s t-tests for continuous variable, and by χ2 test for categorical variables. BMI, body mass index; BSA, body surface area; BP, blood pressure; HR, heart rate; TIA, transient ischaemia attack; IHD, ischaemia heart disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation. Echocardiography Standard resting 2D echocardiographic parameters are summarised in Table 2. Both the inter-ventricular septum and posterior LV wall thickness were significantly higher in the hypertensive group, with no difference in LVEF between the groups. Septal and lateral E/e’ ratios were significantly higher in the hypertensive group both at rest and at low-dose dobutamine (Table 2). Table 2 Echocardiographic characteristics of the study population Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 IVSd, interventricular septal wall thickness at end-diastole; LVIDd, left ventricular internal diameter at end-diastole; PWd, posterior wall thickness at end-diastole; LVIDs, left ventricular internal diameter at end-systole; SD, standard deviation. Table 2 Echocardiographic characteristics of the study population Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 IVSd, interventricular septal wall thickness at end-diastole; LVIDd, left ventricular internal diameter at end-diastole; PWd, posterior wall thickness at end-diastole; LVIDs, left ventricular internal diameter at end-systole; SD, standard deviation. There was no difference in LVEF at low-dose dobutamine between the two groups (Figure 1). There were no significant differences between the two groups in either absolute or relative CR when assessed by LVEF (Table 3). Table 3 LV CR assessment Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 CR, contractile reserve; LVEF, left ventricular ejection fraction; SD, standard deviation. Table 3 LV CR assessment Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 CR, contractile reserve; LVEF, left ventricular ejection fraction; SD, standard deviation. Figure 1 View largeDownload slide LVEF at rest and at low-dose dobutamine. There was no significantly difference in LVEF between normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Figure 1 View largeDownload slide LVEF at rest and at low-dose dobutamine. There was no significantly difference in LVEF between normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Multi-directional strain analysis LV GLS was significantly impaired in the hypertensive group, both at rest and at low-dose dobutamine (Figure 2). While there was no significant difference in circumferential strain between the two groups at rest, circumferential strain was significantly impaired at low-dose dobutamine in hypertensive patients (Figure 3). There were no differences in radial strain between the groups either at rest or at low-dose dobutamine (Figure 4). When assessed by GLS, both the absolute and relative CR were significantly impaired in the hypertensive group compared with the normotensive group (Table 3). There were no differences in absolute or relative CR between the two groups when assessed either by circumferential or radial strain (Table 3). Figure 2 View largeDownload slide LV GLS at rest and at low-dose dobutamine. LV GLS was significantly impaired in the hypertensive group when compared with the normotensive group, both at rest and at low-dose dobutamine infusion. CI, confidence interval. Figure 2 View largeDownload slide LV GLS at rest and at low-dose dobutamine. LV GLS was significantly impaired in the hypertensive group when compared with the normotensive group, both at rest and at low-dose dobutamine infusion. CI, confidence interval. Figure 3 View largeDownload slide LV circumferential strain at rest and at low-dose dobutamine. There was no significant difference in circumferential strain between the normotensive and hypertensive groups at rest; however, circumferential strain was significantly impaired at low-dose dobutamine infusion in the hypertensive group (P = 0.002). CI, confidence interval. Figure 3 View largeDownload slide LV circumferential strain at rest and at low-dose dobutamine. There was no significant difference in circumferential strain between the normotensive and hypertensive groups at rest; however, circumferential strain was significantly impaired at low-dose dobutamine infusion in the hypertensive group (P = 0.002). CI, confidence interval. Figure 4 View largeDownload slide LV radial strain at rest and at low-dose dobutamine. There was no significant difference in radial strain between the normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Figure 4 View largeDownload slide LV radial strain at rest and at low-dose dobutamine. There was no significant difference in radial strain between the normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Six hypertensive patients had normal GLS at rest. However, these patients had significantly impaired GLS at low-dose dobutamine compared with the normotensive group (−19.4 ± 2.8% vs. −22.8 ± 2.6%, P = 0.01). Furthermore, these patients also had significantly impaired CR compared with the normotensive group (−1.0 ± 2.8% vs. −3.2 ± 2.2% and 5.0 ± 5.6% vs. 16.4 ± 11.7% for absolute and relative CR, respectively, both P < 0.001). After patients on β-blockers were excluded (effective n = 84), the results were similar to the original analysis. Compared to normotensive patients, hypertensive patients had significantly impaired GLS at rest (−17.1 ± 1.8% vs. −19.4 ± 1.5%, P < 0.001), and at low-dose dobutamine (−18.1 ± 2.3% vs. −22.6 ± 2.4%, P < 0.001). Hypertensive patients also had impaired relative (6.0 ± 8.7% vs. 16.2 ± 10.8%, P < 0.001) and absolute (−1.0 ± 1.5% vs. −3.1 ± 2.0%, P < 0.001) CR. Correlates of LV systolic strain and CR There was no significant correlation between prevailing resting systolic or diastolic BP and LVEF, either at rest or at low-dose dobutamine. There were no correlations between prevailing BP and CR measured by LVEF. Interventricular septal and LV posterior wall thickness demonstrated a modest correlation with LV GLS at rest (r = 0.227, P = 0.01 and r = 0.271, P = 0.002, respectively), and at low-dose dobutamine (r = 0.289, P = 0.001 and r = 0.312, P < 0.001, respectively). Interventricular septal and LV posterior wall thickness also correlated with absolute CR measured by GLS (r = 0.199, P = 0.024 and r = 0.194, P = 0.028, respectively). Interventricular septal thickness also correlated with CR measured by circumferential strain (r = 0.285, P = 0.001 and r = −0.202, P = 0.025 for absolute and relative CR, respectively). There were significant correlations between prevailing systolic BP and GLS at rest (r = 0.32, P < 0.001) and at low-dose dobutamine (r = 0.33, P < 0.001). However, there was no significant correlation between prevailing BP and CR measured by LV GLS. There was a significant correlation between prevailing diastolic BP and circumferential strain at rest (r = 0.384, P < 0.001), and between systolic and diastolic BP and circumferential strain at low-dose dobutamine (r = 0.283, P = 0.001 and r = 0.239, P = 0.007, respectively). There were no significant correlations between BP and CR measured by circumferential strain. There were no significant correlations between BP and radial strain at rest or at low-dose dobutamine, nor between BP and CR measured by radial strain. Septal and lateral E/e’ ratios at rest had modest correlation with GLS at rest (r = 0.26, P = 0.003 and r = 0.28, P = 0.002, respectively) and at low-dose dobutamine (r = 0.26, P = 0.004 and r = 0.24, P = 0.008, respectively). However, there was no significant correlation between E/e’ ratio at rest or at low-dose dobutamine and either absolute or relative CR. Intra- and inter-observer reproducibility ICC for intra-observer variability was 0.94 for GLS, 0.91 for circumferential strain, and 0.88 for radial strain. ICC for inter-observer variability was 0.87 for GLS, 0.86 for circumferential strain, and 0.40 for radial strain. Discussion In patients with treated hypertension without diabetes or significant coronary artery disease, despite having normal LVEF at rest, subclinical LV systolic impairment was evident when assessed by GLS compared with normotensive patients. Furthermore, hypertensive patients had an impaired ability to augment LV contractility in response to inotropic stimulation by dobutamine, as evident by the impaired GLS at low-dose dobutamine and a reduced CR. GLS at rest and with low-dose dobutamine, and CR correlated with LV wall thickness. In addition, GLS at rest and with low-dose dobutamine correlated with prevailing systolic BP. The impaired CR in hypertensive patients was also evident by significantly impaired circumferential strain at low-dose dobutamine in hypertensive patients compared with normotensive controls, despite no difference in circumferential strain at rest between the groups. This impairment in circumferential strain at low-dose dobutamine correlated with prevailing BP. LV systolic strain in hypertension In this study, we found that LV GLS was significantly impaired in hypertensive patients at rest, with no difference in resting circumferential, radial strain or LVEF, between the groups. Numerous studies have found LVEF to be insensitive in detecting subclinical myocardial dysfunction in a variety of cardiovascular conditions, and only detects abnormalities in an advanced stage of hypertensive heart disease.15 In contrast, strain analysis has proven to be more sensitive and accurate in detecting subclinical myocardial dysfunction.16,17 Previous studies have detected evidence of LV systolic strain impairment in patients with hypertension despite preserved LVEF,4,6,18–21 and before LVH occurs.3–5 Previous studies demonstrating impaired GLS in patients with hypertension used healthy subjects as controls; we used normotensive patients with comparable cardiovascular risk factors. Furthermore, we excluded patients with diabetes and significant coronary artery disease, and therefore were able to examine GLS in a more homogenous patient population, where the only major factor adversely affecting LV deformation was hypertension. Longitudinal myocardial fibres are predominantly located in the subendocardium, and are more vulnerable to ischaemia, hypoxia and higher wall stress associated with haemodynamic overload.22 Therefore, longitudinal function measured by deformation may be affected earlier than the circumferential or radial deformation. Indeed, recent studies have shown evidence of longitudinal strain impairment in the presence of preserved circumferential strain in patients with hypertension.21,23–26 Correlates of LV systolic strain and CR We demonstrated that LV wall thickness is related to LV GLS and CR. Goebel et al.27 examined the effect of LVH on strain parameters in patients with treated hypertension, and found no difference in LV peak longitudinal strain between hypertensive patients with or without LVH. Kouzu et al.26 examined the effect of LVH on strain parameters, and found significantly impaired longitudinal strain in the hypertensive group, with LVH being the only independent correlate. However, LV CR was not examined in any of these studies. A recent publication by Stokke et al.28 examined the impact of geometric factors on LVEF, taking into account four parameters including GLS and circumferential strain, wall thickness, and end-diastolic volume (EDV). Preservation of LVEF in the context of reduced GLS and circumferential strain can be explained by increased LV wall thickness and/or reduced EDV,28 and that circumferential strain had a significantly greater effect than GLS on LVEF. In this study, hypertensive patients had significantly impaired GLS; however, they also had significantly higher LV wall thickness and preservation of circumferential strain at rest, which may explain the overall preservation of LVEF. We found prevailing systolic BP correlated with GLS (both at rest and with low-dose dobutamine) and circumferential strain (with low-dose dobutamine). Strain deformation is a load-dependent parameter, with previous studies demonstrating an inverse correlation between LV pressure load and longitudinal and circumferential strain.29,30 Our results are in keeping with their findings of load-dependence of these deformation parameters. A study by Shin et al.5 found a significant correlation between GLS and average diastolic BP obtained by 24-h ambulatory BP monitoring, but no correlation between GLS and systolic BP. However, their study examined only young adults and only 20% of their participants were women. Our study had a larger sample size, with a wider age range and a higher mean age, and 47.2% were women. Our results are therefore more likely to reflect the real impact of hypertension in the general population. We demonstrated that patients with hypertension had impaired CR when assessed by GLS but not by LVEF. Tan et al.31 performed treadmill exercise echocardiography in hypertensive patients with normal resting LVEF. They found significantly lower GLS in hypertensive patients both at rest and on exercise. However, the hypertensive group in their study had a significantly higher body mass index compared with controls, and a significant percentage of patients (20%) had a history of coronary artery disease and diabetes. Coronary artery disease, diabetes and obesity have all been found to independently affect GLS,32,33 and their results may therefore have been confounded by these co-morbidities in the hypertensive group. In this study, there was no difference in body mass index between the groups, and as both coronary artery disease and diabetes were excluded, our results would be more reflective of the true impact of hypertension on LV systolic deformation. Badran et al.34 assessed LV CR with treadmill exercise echocardiography. They found significantly impaired longitudinal strain at rest and during peak exercise, better circumferential strain at rest but no difference during peak exercise, and a smaller increase in both longitudinal and circumferential strain and impaired reserve with exercise, in hypertensive patients compared to controls. Similar results were also noted by another study by Hensel et al.35 Hypertension is a leading cause of LV diastolic impairment. E/e’ ratio, an estimate of LV filling pressure, is an important parameter in the assessment of LV diastolic performance. Previous studies have found significant correlation between E/e’ ratio and GLS at rest,23 suggesting the coexistence of systolic and diastolic impairment in hypertensive patients. We found significant correlation between E/e’ ratio and GLS at rest. We further examined the relationship between E/e’ ratio and LV CR, and found significant correlation between E/e’ ratio at rest and GLS at low-dose dobutamine. Lateral E/e’ at low-dose dobutamine also correlated with GLS at rest and at low-dose dobutamine. To our knowledge, our study was the first to evaluate the relationship between E/e’ ratio and LV contractile performance with inotropic stimulation. Limitations An important limitation of our study is the relatively small sample size. As the absence of coronary artery disease was a predefined strict exclusion criterion, potential participants were selected from all the patients who had undergone an invasive coronary angiogram. As diabetes and coronary disease are highly prevalent conditions, a significant number of screened subjects had to be excluded. We believe that inclusion of these co-morbidities would have confounded our results as these conditions have all been shown to cause LV systolic impairment. Nonetheless, compared to most of the published studies to assess LV CR, our study had a larger sample size, with strict exclusion criteria determined a priori, to avoid any foreseeable potential confounders. In this study, we only used the prevailing BP which was measured just prior to the commencement of the stress echocardiography. This BP reading may not reflect overall BP control for the patient. Using BP measurements from a 24-h ambulatory BP monitoring would have been more reflective of the overall average BP, but this was beyond the scope of our study. Nonetheless, we did find a significant correlation between systolic BP and GLS both at rest and at low-dose dobutamine. β-blocker treatment may have negative inotropic and chronotropic effect on the left ventricle and its response to dobutamine. We performed the low-dose assessment at 20 μg/kg/min for patients on such treatment, as compared to 10 μg/kg/min for those who were not. We also performed a subanalysis excluding patients on β-blockers, which demonstrated similar results to the whole study population. Conclusion Patients with hypertension and no coexistent diabetes or coronary artery disease, with normal resting LVEF not only have impaired LV GLS at rest but lack CR with low-dose dobutamine. They also have impaired augmentation of circumferential strain with low-dose dobutamine challenge despite normal circumferential strain at rest. The impaired CR correlated with LV wall thickness independent of prevailing blood pressures. Assessment of CR by GLS may have incremental value in diagnosing early and subclinical LV systolic impairment in patients with hypertension. Its prognostic potentialities in hypertensive heart disease needs to be assessed in future longitudinal studies. Acknowledgements We are very grateful to all the patients who have participated in this research project. Conflict of interest: None declared. 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For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Left ventricular function and contractile reserve in patients with hypertension

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jex338
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Abstract

Abstract Aims An impaired contractile reserve (CR) may be an early manifestation of left ventricular (LV) systolic dysfunction in hypertensive patients. Using normotensive patients as controls, we examined LV CR and its correlates in hypertensive patients. Methods and results One hundred and twenty-nine (68 men, aged 58.6 ± 9.5 years, 73 had hypertension) patients underwent dobutamine echocardiography. Patients with significant coronary or valvular disease, previous myocardial infarction or revascularization, and diabetes were excluded. LV ejection fraction (LVEF), global longitudinal strain (GLS), circumferential, and radial strain were measured at rest and at low-dose dobutamine. Absolute CR was calculated as the difference in LVEF and multi-directional strain between low-dose dobutamine and their corresponding resting values. Relative CR is the ratio of absolute CR to their corresponding resting values. Hypertensive patients, compared with controls, have significantly impaired GLS at rest (−16.8 ± 2.2% vs. −19.6 ± 1.5%, P < 0.0001) and at low-dose dobutamine (−17.9 ± 2.7% vs. −22.8 ± 2.6%, P < 0.0001). Absolute and relative GLS CR were significantly lower in hypertensive patients (−1.1 ± 2.1% vs. −3.2 ± 2.2% and 7.4 ± 13.9% vs. 16.4 ± 11.7%, respectively, both P < 0.001). Circumferential strain was preserved at rest but impaired at low-dose dobutamine in hypertensive patients (−23.0 ± 4.1% vs. −25.2 ± 3.4%, P = 0.002). There were no differences in LVEF or radial strain between the groups. LV wall thickness and systolic blood pressure correlated significantly with GLS at rest and at low-dose dobutamine. LV wall thickness is the only independent correlates of absolute CR. Conclusion Compared with controls, hypertensive patients have impaired LV GLS at rest and impaired CR despite normal LVEF. Impaired CR correlated with LV wall thickness but independent of prevailing blood pressure. hypertension, ventricular function, contractile reserve, echocardiography, speckle tracking strain Introduction Hypertension is a prevalent and well-recognised cardiovascular risk factor, which may lead to left ventricular (LV) systolic impairment through chronic pressure overload. LV hypertrophy (LVH) is a compensatory process in response to increased wall stress. However, this initially useful adaptive mechanism later becomes ‘a pathological change’ in the myocardium. Whilst LVH has been shown to be a powerful independent predictor for cardiovascular morbidity and mortality,1,2 it can occur late. Multiple recent studies have shown that LV ejection fraction (LVEF) lacks accuracy and sensitivity in detecting early subclinical impairment. In contrast, LV strain analysis has been proven to be more sensitive in detecting early subclinical LV systolic dysfunction, when the LVEF is still within ‘normal’ limits.3–6 LV systolic dysfunction in the early stage can be subtle and subclinical. Resting systolic function may remain preserved, but contractile reserve (CR) to inotropic stimulation may be blunted. A depressed CR has been documented in patients with aortic stenosis,7 mitral regurgitation,8 aortic regurgitation,9 and in diabetic cardiomyopathy,10 and is thought to represent an early manifestation of LV dysfunction. Similarly, impaired CR may be an early manifestation of LV systolic impairment in hypertensive patients. The aim of this study was to examine CR and its correlates in hypertensive patients and examine the relationship between impaired CR and resting LV systolic function as assessed by LV deformation. A group of normotensive patients was recruited as controls. Methods Study population Patients who were referred for invasive coronary angiogram were screened for suitability of recruitment into the study. Patients with significant coronary artery disease, defined as >50% stenosis in any major epicardial coronary arteries or its major branches on coronary angiography, were excluded. Other exclusion criteria included non-sinus rhythm, left bundle branch block, coexisting significant left sided valvular heart disease (more than mild in severity), diabetes mellitus, previous myocardial infarction, or coronary revascularisation. One hundred and thirty-two patients were prospectively recruited into the study. Three patients were subsequently excluded due to poor image quality, 129 patients were included in the final analysis. Seventy three (56%) patients had treated hypertension. This research study was approved by the Human Research Ethics Committee of the South Western Sydney Local Health District, and written informed consent was obtained from all participants. Echocardiography A comprehensive transthoracic echocardiogram with appropriate 2D, colour, and Doppler imaging were performed from standard transthoracic imaging windows using commercially available ultrasound machine Vivid E9 (GE Medical Systems, Horten, Norway). Zoomed LV views were obtained at high frame rates (≥70 frame/s) from the apical four-, two-, and three-chambers, as well as parasternal short-axis views at the papillary muscle level for optimal speckle-tracking strain analysis. All studies were digitally stored and analysed off-line. LV wall thickness and biplane modified Simpson’s LVEF were measured using standard recommendations for LV chamber quantification.11 Dobutamine stress echocardiography Dobutamine stress echocardiography was performed in all participants according to standard protocol. Intravenous dobutamine was infused in incremental doses starting at 5 µg/kg/min. The dose was then increased to 10 µg/kg/min and 20 µg/kg/min at 3 min interval. Standard parasternal long- and short-axis views, and apical four-, two-, and three-chamber views of the left ventricle were obtained at rest and at the end of each infusion stage. Patients who were on β-blockers or non-dihydropyridine calcium blockers had their low-dose echocardiography assessment performed at 20 µg/kg/min; for the remaining patients, the low-dose assessment was performed at 10 µg/kg/min. These doses were chosen as they have been previously demonstrated to be safe and effective in detecting CR, without affecting heart rate, blood pressure (BP), or loading conditions.12,13 Visual wall motion analysis was performed by an experienced investigator using the American Society of Echocardiography’s 16 segment model in a blinded fashion.11 2D multi-directional speckle tracking strain analysis The 2D speckle tracking strain analyses were performed on grey scale images of the left ventricle using Echopac (Version BT13, GE Medical Systems). Peak global systolic longitudinal strain was measured from the 18 segment measurements (six segments from each of the apical four-, two-, and three-chamber views). Peak systolic circumferential and radial strain were measured from the six segments in the parasternal short-axis view of the left ventricle at the papillary muscle level. The Echopac software provided both global and segmental strain values but only the global strain values were included in the analysis. During strain analysis, the endocardial border was manually traced at end-systole, and the width of the region of interest manually adjusted to include the entire myocardial wall thickness. The Echopac software then automatically tracks and accepts segments with good tracking quality and rejects poorly tracked segments. The operator was able to manually override computer-generated tracking and accept or reject individual segments based on visual assessments of the tracking quality. Three cardiac cycles were analysed and the measurements averaged. Normal resting peak global longitudinal strain (GLS) was defined as less than −20% based on previously published literature.11 Assessment of LV CR LVEF and strain analysis were performed both at rest and at low-dose dobutamine. Absolute CR was calculated as the difference in LVEF and multi-directional strain between the low-dose and their corresponding resting values. Relative CR was defined as the ratio of absolute CR to the corresponding resting values, and expressed as percentage. Impaired CR was defined as an absolute CR of ≤5% as measured by LVEF.14 Statistical analysis All continuous variables are reported as the mean ± 1 standard deviation unless otherwise stated. Categorical variables are presented as frequencies and percentages. All continuous variables were evaluated for normality of distribution to ensure the assumptions of subsequent tests were met. Paired student’s t-test was used to compare the results from the baseline and low-dose dobutamine for each subject. The χ2 test was used for evaluation of categorical variables. Linear correlation between strain and echocardiographic measurements were assessed using Pearson correlation coefficients. P-values of ≤0.05 were considered significant. All statistical analyses were performed using SPSS for Windows (IBM SPSS Statistics, version 23). Intra-observer and inter-observer variability analysis Strain analyses were repeated in 10 randomly selected patients at least 4 weeks after the initial analysis by the original investigator and by a second investigator, both blinded to the original measurements, to assess intra-observer and inter-observer variability, respectively. Intra-class correlation (ICC) was evaluated. Results Patient characteristics One hundred twenty-nine patients were included in this study (68 men, aged 58.6 ± 9.5 years), with 73 (56%) patients having treated hypertension. Baseline demographic and clinical characteristics are summarized in Table 1. The normotensive group tended to be younger. There were no statistically significant differences in the gender, body mass index, body surface area, or prevalence of background cardiovascular risk factor profile between the groups, except for hypertension by virtue of the study design. This is also reflected in the differences in the use of antihypertensive medications. Table 1 Demographic and clinical characteristics of the study population Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 P-values comparing hypertensive patients with normotensive controls, by independent sample’s t-tests for continuous variable, and by χ2 test for categorical variables. BMI, body mass index; BSA, body surface area; BP, blood pressure; HR, heart rate; TIA, transient ischaemia attack; IHD, ischaemia heart disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation. Table 1 Demographic and clinical characteristics of the study population Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 Normotensive (n = 56) Hypertensive (n = 73) P-value Demographic characteristics  Age (years), mean ± SD 56.7 ± 10.2 60.0 ± 8.7 0.051  Male (%) 57.9 48.6 0.294  BMI (kg/m2), mean ± SD 27.8 ± 4.4 29.0 ± 4.4 0.128  BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 0.871 Clinical characteristics  Systolic BP at rest (mmHg), mean ± SD 129.1 ± 11.6 143.9 ± 16.3 <0.01  Diastolic BP at rest (mmHg), mean ± SD 80.1 ± 8.6 84.0 ± 12.7 0.034 HR at rest (b.p.m), mean ± SD 64.2 ± 9.0 65.3 ± 10.5 0.525  Systolic BP at low-dose dobutamine (mmHg), mean ± SD 131.1 ± 14.5 143.8 ± 20.0 <0.001  Diastolic BP at low-dose dobutamine (mmHg), mean±SD 79.3 ± 11.5 85.1 ± 14.4 0.016  HR at low-dose dobutamine (b.p.m), mean ± SD 63.0 ± 9.0 64.3 ± 11.1 0.477  Hypercholesterolaemia (%) 66.1 71.2 0.53  Smoking status (%) 0.973   Never 30.4 31.5   Current 19.6 20.5   Ex-smoker 50.0 47.9  History of stroke or TIA (%) 5.4 8.2 0.73  Family history of IHD (%) 62.5 50.7 0.18 Medications (%)  Aspirin 46.4 56.2 0.296  β-blockers 23.2 43.8 0.011  Calcium channel blockers 3.6 27.4 <0.01  ACEI 0 23.3 <0.01  ARB 0 46.6 <0.01  Statin 51.8 67.1 0.05  Ezetimibe 3.6 6.8 0.415  Diuretics 0 20.5 <0.01 P-values comparing hypertensive patients with normotensive controls, by independent sample’s t-tests for continuous variable, and by χ2 test for categorical variables. BMI, body mass index; BSA, body surface area; BP, blood pressure; HR, heart rate; TIA, transient ischaemia attack; IHD, ischaemia heart disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation. Echocardiography Standard resting 2D echocardiographic parameters are summarised in Table 2. Both the inter-ventricular septum and posterior LV wall thickness were significantly higher in the hypertensive group, with no difference in LVEF between the groups. Septal and lateral E/e’ ratios were significantly higher in the hypertensive group both at rest and at low-dose dobutamine (Table 2). Table 2 Echocardiographic characteristics of the study population Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 IVSd, interventricular septal wall thickness at end-diastole; LVIDd, left ventricular internal diameter at end-diastole; PWd, posterior wall thickness at end-diastole; LVIDs, left ventricular internal diameter at end-systole; SD, standard deviation. Table 2 Echocardiographic characteristics of the study population Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 Variables Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-value IVSd (cm) 1.0 ± 0.2 1.1 ± 0.2 0.003 LVIDd (cm) 4.6 ± 0.4 4.6 ± 0.5 0.9 PWd (cm) 1.0 ± 0.2 1.1 ± 0.1 0.001 LVIDs (cm) 2.6 ± 0.4 2.9 ± 0.6 0.119 LVEF (%)  Resting 64.5 ± 6.6 64.5 ± 6.0 0.986  Low-dose dobutamine 71.2 ± 7.0 72.1 ± 6.5 0.424 E velocity (cm/s) 68.5 ± 15.8 71.9 ± 16.7 0.236 A velocity (cm/s) 62.1 ± 14.7 73.9 ± 14.4 <0.01 Mitral E/A ratio 1.2 ± 0.3 1.0 ± 0.2 0.001 Mitral E deceleration time (ms) 221.6 ± 51.7 221.9 ± 45.0 0.977 e’ septal 6.5 ± 1.7 5.8 ± 1.8 0.013 e’ lateral 7.6 ± 3.0 6.6 ± 1.8 0.021 E/e’ septal 11.1 ± 3.7 13.3 ± 4.5 0.003 E/e’ lateral 9.9 ± 3.9 11.6 ± 3.9 0.017 At low-dose dobutamine  E/e’ septal 12.7 ± 3.6 14.5 ± 4.3 0.031  E/e’ lateral 11.1 ± 3.7 13.7 ± 4.5 0.003 IVSd, interventricular septal wall thickness at end-diastole; LVIDd, left ventricular internal diameter at end-diastole; PWd, posterior wall thickness at end-diastole; LVIDs, left ventricular internal diameter at end-systole; SD, standard deviation. There was no difference in LVEF at low-dose dobutamine between the two groups (Figure 1). There were no significant differences between the two groups in either absolute or relative CR when assessed by LVEF (Table 3). Table 3 LV CR assessment Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 CR, contractile reserve; LVEF, left ventricular ejection fraction; SD, standard deviation. Table 3 LV CR assessment Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 Parameter Normotensive (n = 56), mean ± SD Hypertensive (n = 73), mean ± SD P-values Longitudinal strain (%)  Absolute CR −3.2 ± 2.2 −1.1 ± 2.1 <0.001  Relative CR 16.4 ± 11.7 7.4 ± 13.9 <0.001 Circumferential strain (%)  Absolute CR −4.1 ± 4.8 −3.3 ± 3.8 0.275  Relative CR 24.1 ± 21.5 18.8 ± 21.2 0.176 Radial strain (%)  Absolute CR −0.35 ± 11.4 −2.9 ± 16.4 0.332  Relative CR 5.1 ± 47.9 13.3 ± 62.9 0.421 LVEF (%)  Absolute CR 6.8 ± 5.1 7.5 ± 5.3 0.447  Relative CR 11.0 ± 8.7 12.0 ± 9.0 0.500 CR, contractile reserve; LVEF, left ventricular ejection fraction; SD, standard deviation. Figure 1 View largeDownload slide LVEF at rest and at low-dose dobutamine. There was no significantly difference in LVEF between normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Figure 1 View largeDownload slide LVEF at rest and at low-dose dobutamine. There was no significantly difference in LVEF between normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Multi-directional strain analysis LV GLS was significantly impaired in the hypertensive group, both at rest and at low-dose dobutamine (Figure 2). While there was no significant difference in circumferential strain between the two groups at rest, circumferential strain was significantly impaired at low-dose dobutamine in hypertensive patients (Figure 3). There were no differences in radial strain between the groups either at rest or at low-dose dobutamine (Figure 4). When assessed by GLS, both the absolute and relative CR were significantly impaired in the hypertensive group compared with the normotensive group (Table 3). There were no differences in absolute or relative CR between the two groups when assessed either by circumferential or radial strain (Table 3). Figure 2 View largeDownload slide LV GLS at rest and at low-dose dobutamine. LV GLS was significantly impaired in the hypertensive group when compared with the normotensive group, both at rest and at low-dose dobutamine infusion. CI, confidence interval. Figure 2 View largeDownload slide LV GLS at rest and at low-dose dobutamine. LV GLS was significantly impaired in the hypertensive group when compared with the normotensive group, both at rest and at low-dose dobutamine infusion. CI, confidence interval. Figure 3 View largeDownload slide LV circumferential strain at rest and at low-dose dobutamine. There was no significant difference in circumferential strain between the normotensive and hypertensive groups at rest; however, circumferential strain was significantly impaired at low-dose dobutamine infusion in the hypertensive group (P = 0.002). CI, confidence interval. Figure 3 View largeDownload slide LV circumferential strain at rest and at low-dose dobutamine. There was no significant difference in circumferential strain between the normotensive and hypertensive groups at rest; however, circumferential strain was significantly impaired at low-dose dobutamine infusion in the hypertensive group (P = 0.002). CI, confidence interval. Figure 4 View largeDownload slide LV radial strain at rest and at low-dose dobutamine. There was no significant difference in radial strain between the normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Figure 4 View largeDownload slide LV radial strain at rest and at low-dose dobutamine. There was no significant difference in radial strain between the normotensive and hypertensive groups either at rest or at low-dose dobutamine infusion. CI, confidence interval. Six hypertensive patients had normal GLS at rest. However, these patients had significantly impaired GLS at low-dose dobutamine compared with the normotensive group (−19.4 ± 2.8% vs. −22.8 ± 2.6%, P = 0.01). Furthermore, these patients also had significantly impaired CR compared with the normotensive group (−1.0 ± 2.8% vs. −3.2 ± 2.2% and 5.0 ± 5.6% vs. 16.4 ± 11.7% for absolute and relative CR, respectively, both P < 0.001). After patients on β-blockers were excluded (effective n = 84), the results were similar to the original analysis. Compared to normotensive patients, hypertensive patients had significantly impaired GLS at rest (−17.1 ± 1.8% vs. −19.4 ± 1.5%, P < 0.001), and at low-dose dobutamine (−18.1 ± 2.3% vs. −22.6 ± 2.4%, P < 0.001). Hypertensive patients also had impaired relative (6.0 ± 8.7% vs. 16.2 ± 10.8%, P < 0.001) and absolute (−1.0 ± 1.5% vs. −3.1 ± 2.0%, P < 0.001) CR. Correlates of LV systolic strain and CR There was no significant correlation between prevailing resting systolic or diastolic BP and LVEF, either at rest or at low-dose dobutamine. There were no correlations between prevailing BP and CR measured by LVEF. Interventricular septal and LV posterior wall thickness demonstrated a modest correlation with LV GLS at rest (r = 0.227, P = 0.01 and r = 0.271, P = 0.002, respectively), and at low-dose dobutamine (r = 0.289, P = 0.001 and r = 0.312, P < 0.001, respectively). Interventricular septal and LV posterior wall thickness also correlated with absolute CR measured by GLS (r = 0.199, P = 0.024 and r = 0.194, P = 0.028, respectively). Interventricular septal thickness also correlated with CR measured by circumferential strain (r = 0.285, P = 0.001 and r = −0.202, P = 0.025 for absolute and relative CR, respectively). There were significant correlations between prevailing systolic BP and GLS at rest (r = 0.32, P < 0.001) and at low-dose dobutamine (r = 0.33, P < 0.001). However, there was no significant correlation between prevailing BP and CR measured by LV GLS. There was a significant correlation between prevailing diastolic BP and circumferential strain at rest (r = 0.384, P < 0.001), and between systolic and diastolic BP and circumferential strain at low-dose dobutamine (r = 0.283, P = 0.001 and r = 0.239, P = 0.007, respectively). There were no significant correlations between BP and CR measured by circumferential strain. There were no significant correlations between BP and radial strain at rest or at low-dose dobutamine, nor between BP and CR measured by radial strain. Septal and lateral E/e’ ratios at rest had modest correlation with GLS at rest (r = 0.26, P = 0.003 and r = 0.28, P = 0.002, respectively) and at low-dose dobutamine (r = 0.26, P = 0.004 and r = 0.24, P = 0.008, respectively). However, there was no significant correlation between E/e’ ratio at rest or at low-dose dobutamine and either absolute or relative CR. Intra- and inter-observer reproducibility ICC for intra-observer variability was 0.94 for GLS, 0.91 for circumferential strain, and 0.88 for radial strain. ICC for inter-observer variability was 0.87 for GLS, 0.86 for circumferential strain, and 0.40 for radial strain. Discussion In patients with treated hypertension without diabetes or significant coronary artery disease, despite having normal LVEF at rest, subclinical LV systolic impairment was evident when assessed by GLS compared with normotensive patients. Furthermore, hypertensive patients had an impaired ability to augment LV contractility in response to inotropic stimulation by dobutamine, as evident by the impaired GLS at low-dose dobutamine and a reduced CR. GLS at rest and with low-dose dobutamine, and CR correlated with LV wall thickness. In addition, GLS at rest and with low-dose dobutamine correlated with prevailing systolic BP. The impaired CR in hypertensive patients was also evident by significantly impaired circumferential strain at low-dose dobutamine in hypertensive patients compared with normotensive controls, despite no difference in circumferential strain at rest between the groups. This impairment in circumferential strain at low-dose dobutamine correlated with prevailing BP. LV systolic strain in hypertension In this study, we found that LV GLS was significantly impaired in hypertensive patients at rest, with no difference in resting circumferential, radial strain or LVEF, between the groups. Numerous studies have found LVEF to be insensitive in detecting subclinical myocardial dysfunction in a variety of cardiovascular conditions, and only detects abnormalities in an advanced stage of hypertensive heart disease.15 In contrast, strain analysis has proven to be more sensitive and accurate in detecting subclinical myocardial dysfunction.16,17 Previous studies have detected evidence of LV systolic strain impairment in patients with hypertension despite preserved LVEF,4,6,18–21 and before LVH occurs.3–5 Previous studies demonstrating impaired GLS in patients with hypertension used healthy subjects as controls; we used normotensive patients with comparable cardiovascular risk factors. Furthermore, we excluded patients with diabetes and significant coronary artery disease, and therefore were able to examine GLS in a more homogenous patient population, where the only major factor adversely affecting LV deformation was hypertension. Longitudinal myocardial fibres are predominantly located in the subendocardium, and are more vulnerable to ischaemia, hypoxia and higher wall stress associated with haemodynamic overload.22 Therefore, longitudinal function measured by deformation may be affected earlier than the circumferential or radial deformation. Indeed, recent studies have shown evidence of longitudinal strain impairment in the presence of preserved circumferential strain in patients with hypertension.21,23–26 Correlates of LV systolic strain and CR We demonstrated that LV wall thickness is related to LV GLS and CR. Goebel et al.27 examined the effect of LVH on strain parameters in patients with treated hypertension, and found no difference in LV peak longitudinal strain between hypertensive patients with or without LVH. Kouzu et al.26 examined the effect of LVH on strain parameters, and found significantly impaired longitudinal strain in the hypertensive group, with LVH being the only independent correlate. However, LV CR was not examined in any of these studies. A recent publication by Stokke et al.28 examined the impact of geometric factors on LVEF, taking into account four parameters including GLS and circumferential strain, wall thickness, and end-diastolic volume (EDV). Preservation of LVEF in the context of reduced GLS and circumferential strain can be explained by increased LV wall thickness and/or reduced EDV,28 and that circumferential strain had a significantly greater effect than GLS on LVEF. In this study, hypertensive patients had significantly impaired GLS; however, they also had significantly higher LV wall thickness and preservation of circumferential strain at rest, which may explain the overall preservation of LVEF. We found prevailing systolic BP correlated with GLS (both at rest and with low-dose dobutamine) and circumferential strain (with low-dose dobutamine). Strain deformation is a load-dependent parameter, with previous studies demonstrating an inverse correlation between LV pressure load and longitudinal and circumferential strain.29,30 Our results are in keeping with their findings of load-dependence of these deformation parameters. A study by Shin et al.5 found a significant correlation between GLS and average diastolic BP obtained by 24-h ambulatory BP monitoring, but no correlation between GLS and systolic BP. However, their study examined only young adults and only 20% of their participants were women. Our study had a larger sample size, with a wider age range and a higher mean age, and 47.2% were women. Our results are therefore more likely to reflect the real impact of hypertension in the general population. We demonstrated that patients with hypertension had impaired CR when assessed by GLS but not by LVEF. Tan et al.31 performed treadmill exercise echocardiography in hypertensive patients with normal resting LVEF. They found significantly lower GLS in hypertensive patients both at rest and on exercise. However, the hypertensive group in their study had a significantly higher body mass index compared with controls, and a significant percentage of patients (20%) had a history of coronary artery disease and diabetes. Coronary artery disease, diabetes and obesity have all been found to independently affect GLS,32,33 and their results may therefore have been confounded by these co-morbidities in the hypertensive group. In this study, there was no difference in body mass index between the groups, and as both coronary artery disease and diabetes were excluded, our results would be more reflective of the true impact of hypertension on LV systolic deformation. Badran et al.34 assessed LV CR with treadmill exercise echocardiography. They found significantly impaired longitudinal strain at rest and during peak exercise, better circumferential strain at rest but no difference during peak exercise, and a smaller increase in both longitudinal and circumferential strain and impaired reserve with exercise, in hypertensive patients compared to controls. Similar results were also noted by another study by Hensel et al.35 Hypertension is a leading cause of LV diastolic impairment. E/e’ ratio, an estimate of LV filling pressure, is an important parameter in the assessment of LV diastolic performance. Previous studies have found significant correlation between E/e’ ratio and GLS at rest,23 suggesting the coexistence of systolic and diastolic impairment in hypertensive patients. We found significant correlation between E/e’ ratio and GLS at rest. We further examined the relationship between E/e’ ratio and LV CR, and found significant correlation between E/e’ ratio at rest and GLS at low-dose dobutamine. Lateral E/e’ at low-dose dobutamine also correlated with GLS at rest and at low-dose dobutamine. To our knowledge, our study was the first to evaluate the relationship between E/e’ ratio and LV contractile performance with inotropic stimulation. Limitations An important limitation of our study is the relatively small sample size. As the absence of coronary artery disease was a predefined strict exclusion criterion, potential participants were selected from all the patients who had undergone an invasive coronary angiogram. As diabetes and coronary disease are highly prevalent conditions, a significant number of screened subjects had to be excluded. We believe that inclusion of these co-morbidities would have confounded our results as these conditions have all been shown to cause LV systolic impairment. Nonetheless, compared to most of the published studies to assess LV CR, our study had a larger sample size, with strict exclusion criteria determined a priori, to avoid any foreseeable potential confounders. In this study, we only used the prevailing BP which was measured just prior to the commencement of the stress echocardiography. This BP reading may not reflect overall BP control for the patient. Using BP measurements from a 24-h ambulatory BP monitoring would have been more reflective of the overall average BP, but this was beyond the scope of our study. Nonetheless, we did find a significant correlation between systolic BP and GLS both at rest and at low-dose dobutamine. β-blocker treatment may have negative inotropic and chronotropic effect on the left ventricle and its response to dobutamine. We performed the low-dose assessment at 20 μg/kg/min for patients on such treatment, as compared to 10 μg/kg/min for those who were not. We also performed a subanalysis excluding patients on β-blockers, which demonstrated similar results to the whole study population. Conclusion Patients with hypertension and no coexistent diabetes or coronary artery disease, with normal resting LVEF not only have impaired LV GLS at rest but lack CR with low-dose dobutamine. They also have impaired augmentation of circumferential strain with low-dose dobutamine challenge despite normal circumferential strain at rest. The impaired CR correlated with LV wall thickness independent of prevailing blood pressures. Assessment of CR by GLS may have incremental value in diagnosing early and subclinical LV systolic impairment in patients with hypertension. Its prognostic potentialities in hypertensive heart disease needs to be assessed in future longitudinal studies. Acknowledgements We are very grateful to all the patients who have participated in this research project. Conflict of interest: None declared. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Jan 2, 2018

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