The impact of hypertension on systolic and diastolic left ventricular function. A tissue Doppler echocardiographic study

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1 The impact of hypertension on systolic and diastolic left ventricular function. A tissue Doppler echocardiographic study Manolis Bountioukos, MD, PhD, a Arend F.L. Schinkel, MD, PhD, a Jeroen J. Bax, MD, PhD, b Stylianos Lampropoulos, MD, c and Don Poldermans, MD, PhD a Rotterdam, and Leiden, The Netherlands; and Kozani City, Greece Background The purpose of this study is to assess the impact of hypertension on systolic function and diastolic function using 2-dimensional echocardiography, conventional Doppler imaging of the transmitral inflow, and tissue Doppler imaging (TDI) of the mitral annulus. Methods From an outpatient clinic population, 414 consecutive patients underwent 2-dimensional echocardiography, conventional Doppler imaging of the transmitral inflow, and TDI of the septal, lateral, inferior, and posterior walls near the mitral annulus. Parameters of systolic left ventricular (LV) function and diastolic LV function were assessed. Patients were divided according to the presence or absence of systemic hypertension (blood pressure z140/90 mm Hg on z3 measurements or treatment with antihypertensive medication). Results A complete echocardiographic evaluation was obtained in 397 patients. Among these, 269 (68%) had hypertension. There was no difference with respect to age between patients with and without hypertension. Patients with hypertension had higher LV mass index and relative wall thickness and lower TDI peak systolic velocity (V S ) when compared with patients without hypertension. In addition, indices of diastolic LV function were significantly impaired in hypertensive patients. Conclusions Quantitative echocardiography using TDI reveals that hypertensive patients with preserved global LV systolic function often have combined impairment of systolic function and diastolic function. (Am Heart J 2006;151: 1323.e e12.) The prevalence of systemic hypertension in the Western world is approximately 25% and increases considerably with advancing age. 1,2 Hypertension is a risk factor for myocardial infarction, stroke, renal failure, progressive atherosclerosis, and dementia. 3 Moreover, in patients with hypertension and preserved left ventricular (LV) systolic function, hypertension has been linked to a gradual development of diastolic LV dysfunction, referred to as diastolic heart failure. 4 This condition is characterized by a gradual deterioration of myocardial relaxation and, if hypertension is left untreated, development of concentric hypertrophy and increased LV end-diastolic pressure. Numerous studies From the a Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands, b Department of Cardiology, University of Leiden, Leiden, The Netherlands, and c Department of Cardiology, General Hospital of Kozani City, Kozani City, Greece. Submitted November 22, 2005; accepted February 5, Reprint requests: Don Poldermans, MD, PhD, Thoraxcenter Room Ba 300, Department of Cardiology, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. bountioukos@yahoo.com /$ - see front matter n 2006, Published by Mosby, Inc. doi: /j.ahj have focused on (subclinical) diastolic dysfunction in patients with hypertension and preserved global LV systolic function; however, in these studies, systolic function was not assessed quantitatively. Therefore, the impact of hypertension on myocardial systolic function in these patients is currently not clear. Several noninvasive techniques have been used to assess and quantify systolic LV function and diastolic LV function, such as conventional Doppler imaging (CDI) and tissue Doppler imaging (TDI) of the mitral annulus. 5,6 In addition, the combination of mitral inflow and TDI early velocity curves can reliably evaluate the presence of elevated LV end-diastolic pressure. 7 The aim of this study is to assess the impact of hypertension on both systolic function and diastolic function using quantitative echocardiography in patients with preserved global LV systolic function. Methods Patient selection The study included 414 consecutive patients from an outpatient clinic population. Patients with known coronary

2 1323.e8 Bountioukos et al American Heart Journal June 2006 artery disease, cardiac arrhythmias, hypertrophic cardiomyopathy, valvular heart disease, abnormal LV ejection fraction (LVEF b55%), and pulmonary disease were not included. All patients gave informed consent before the test. The local medical ethics committee approved the study protocol. A structured clinical interview and history were acquired, and cardiac risk factors were assessed before echocardiography. Hypertension was defined as abnormal blood pressure (systolic pressure z140 mm Hg and/or diastolic pressure z90 mm Hg in at least 3 measurements 1 week apart each other) or treatment with antihypertensive medication. 8 Two-dimensional echocardiography to assess resting contractile function A commercially available imaging system with a 1.7-MHz transducer using second harmonic imaging to optimize endocardial border visualization was used. 9 All patients underwent a standard echocardiographic examination in the left lateral position; standard views were recorded. The LVEF was determined off-line by the 2-dimensional (2D) biplane disk method using the modified Simpson rule. 10 The endocardial borders of the 2- and 4-chamber apical views were digitally traced at end diastole and end systole. Subsequently, the LV end-diastolic volume and end-systolic volume were derived, and the LVEF was calculated. An LVEF of b55% was considered abnormal. Patients with abnormal LVEF were not included in the study, per enrolment criteria. Echocardiographic assessment of LV mass index and relative wall thickness The following parameters on the M-mode echocardiogram were assessed: LV internal dimension, interventricular septum thickness, and LV posterior wall thickness. Left ventricular mass was calculated using the computer software. The LV mass index (LVMI, g/m 2 ) was defined as LV mass (g) divided by body surface area (m 2 ). Relative wall thickness (RWT) was derived by the following formula: RWT = (2 posterior wall thickness)/lv internal dimension. 11 Pulsed-wave Doppler of mitral valve inflow Pulsed-wave Doppler echocardiography was used to evaluate diastolic LV function as described previously. 12 Doppler studies were recorded from the apical 4-chamber view, with a 2-mm 3 -sized sample volume positioned within the inflow portion of the LV, midway between the annular margins of the mitral valve. Mitral velocity profiles were digitized from the modal velocity of the Doppler tracings. The peak E (early rapid ventricular filling) and peak A (atrial-assisted filling) wave velocities were computed to calculate the E/A velocity ratio. The isovolumic relaxation time (IVRT) was assessed with the transducer angulated into the apical 5-chamber view and the sample volume placed within the LV outflow tract, but in proximity to the anterior mitral valve leaflet, to record both inflow and outflow signals. Measurements of the deceleration time (DT) were made by computer software by placing the caliper to the peak of the E wave and by following the deceleration slope of the E wave down to the intersection with the A wave. The mean value of 5 consecutive normal beats was calculated. Table I. Baseline patient characteristics Patients with hypertension (n = 269) Patients without hypertension (n = 128) P Male 148 (55) 77 (60) NS Age (y) 57 F F 9 NS LVEF 66 F F 7 NS LVMI (g/m 2 ) 112 F F 23 b.05 RWT 0.44 F F 0.1 b.05 Hyperlipidemia 104 (39) 42 (33) NS Diabetes 46 (17) 13 (10) NS Currently smoking 68 (25) 40 (31) NS Medications Angiotensin-converting 84 (31) b.05 enzyme inhibitors Angiotensin II receptor 51 (19) b.05 antagonists h-blockers 74 (28) 9 (7) b.05 Calcium antagonists 76 (28) b.05 Diuretics 34 (13) b.05 Values are expressed as number (%) or mean F SD. Pulsed-wave tissue Doppler imaging Pulsed-wave TDI was used to assess systolic and diastolic myocardial velocities. 13 A pulse repetition frequency of 45 to 60 KHz and a sample volume of 4 mm 3 were used. The measurement of myocardial velocities was sampled in 2 apical views (4- and 2-chamber) close to the mitral annulus and during a minimum of 5 consecutive beats to minimize the variability induced by respiration. All measurements were performed offline using a computer-assisted drawing system. The velocity values (cm/s) were obtained on calibrated still frames by manually measuring the distance between the zero baselines and the peak Doppler profile of the ejection phase and of the early and late diastolic phases in reference to the electrocardiogram. Cardiac cycles with extrasystolic, postextrasystolic beats, or rhythm disturbance were excluded. Statistical analysis Results are expressed as the mean F SD, and percentages are rounded. Statistical analysis was performed using the SPSS program, version for Windows (SPSS, Chicago, IL). Changes of continuous variables in the same group were tested for significance by a paired 2-tailed t test, whereas an independent-samples t test was used to compare continuous variables in different groups. Differences in categorical variables were assessed by the Pearson m 2 test. P b.05 was considered to be statistically significant. Results Demographics Clinical data are reported in Table I. Interpretation and measurement of transmitral inflow velocity signals and TDI velocity signals was feasible in 397 patients (96%). There were 269 patients with hypertension (68%) and 128 patients without hypertension (32%).

3 American Heart Journal Volume 151, Number 6 Bountioukos et al 1323.e9 Figure 1 Figure 3 Left ventricular geometry patterns in hypertensive patients (n = 269). Figure 2 Pulsed-wave tissue Doppler of regional longitudinal motion in a hypertensive patient. The upper panel shows the sample position used to record velocities from the basal lateral wall near the mitral annulus. The lower panel shows the velocity waveforms obtained. V S is abnormally low (6.5 cm/s), and V E is less than V A. Differences in TDI systolic velocity (V S ), early (V E ), and late (V A ) diastolic velocities, and the early diastolic mitral inflow velocity (E) to V E (E/V E ) ratio in patients with and without hypertension. Values are expressed in cm/s ( P b.05). Assessment of LV geometry Hypertensive patients had significantly higher LVMI (112 F 28 vs 99 F 23 g/cm 2, respectively, P b.0001) and RWT (0.44 F 0.1 vs 0.42 F 0.1, respectively, P =.006) compared with patients without hypertension. The categorization of LV geometry patterns of hypertensive patients according to Frohlich et al 11 is shown in Figure 1. Assessment of systolic function Global LV systolic function (LVEF) was preserved in all patients and was comparable in patients with and without hypertension (LVEF 66% F 10% vs 65% F 7%, P = NS). Quantitative assessment of systolic LV function assessed by TDI revealed that patients with hypertension had significantly lower myocardial systolic velocities compared with patients without hypertension (9.1 F 1.6 vs 9.5 F 1.5 cm/s, P =.02) (Figure 2). Abnormal regional systolic function (mean V S value b8.5 m/s) was present in 92 hypertensive patients (34%) and 27 patients without hypertension (21%) ( P =.01). Assessment of diastolic function Transmitral late peak diastolic velocity differed significantly between patients with and without hypertension (72.3 F 21.1 vs 85.9 F 20.5 cm/s, respectively, P b.005). Accordingly, the E/A ratio was lower in patients with hypertension compared with patients without hypertension (1.0 F 0.3 vs 1.2 F 0.4, respectively, P b.005). In hypertensive patients, IVRT and DT were significantly higher compared with patients without hypertension (IVRT 120 F 27 vs 112 F 26 ms, P =.01, and DT 181 F 37 vs 163 F 26 ms, P b.05, respectively). Quantitative assessment of diastolic function using TDI demonstrated that early diastolic velocity (V E )in hypertensive patients was significantly lower compared with patients without hypertension (10.6 F 2.6 cm/s vs 12.6 F 2.7 cm/s, respectively, P b.05). In addition, V E /V A ratio was significantly lower in patients with hypertension (1.0 F0.3 vs 1.2 F 0.3 in patients without hypertension, P b.05). Finally, the E/V E ratio, which is directly related to LV end-diastolic filling pressure, was significantly higher in hypertensive patients compared with patients without hypertension (7.9 F 2.0 vs 6.6 F 1.7, respectively, P b.005) (Figure 2). Figures 3 and 4 demonstrate the differences in systolic and diastolic TDI velocities in a hypertensive study patient and a study patient without hypertension, respectively.

4 1323.e10 Bountioukos et al American Heart Journal June 2006 Figure 4 Pulsed-wave tissue Doppler of regional longitudinal motion in a patient without hypertension. The upper panel shows the sample position used to record velocities from the basal lateral wall near the mitral annulus. The lower panel shows the velocity waveforms obtained. V S is normal (10 cm/s), and V E is higher than V A. Discussion Hypertension is characterized by a gradual increase in LV mass, which may result in concentric hypertrophy and diastolic dysfunction due to LV stiffness with impaired relaxation. If hypertension is treated suboptimally, LV end-diastolic pressures may rise gradually, leading to a condition known as diastolic heart failure. This condition of heart failure in patients with preserved global LV systolic function is associated with significant annual mortality 14,15 and similar reductions in quality of life and exercise performance as compared with systolic heart failure. 16 It is likely that a timely identification of patients with early diastolic abnormalities can favorably impact survival. 17 In the present study, the quantitative assessment of systolic LV function and diastolic LV function was compared in patients with and without hypertension who had a preserved global LV systolic function. In an outpatient clinic patient population, CDI and TDI demonstrated that patients with hypertension had an impaired LV relaxation and elevated LV end-diastolic pressure, expressed by the E/V E ratio. 18 Moreover, there was a significant difference in systolic myocardial velocities assessed by TDI in patients with preserved global LV systolic function, according to the presence or absence of hypertension. Quantitative echocardiography showed that impaired diastolic relaxation is accompanied by impaired systolic velocities in patients with hypertension and preserved global LV systolic function. This systolic impairment is not detectable by conventional echocardiography and may in part be related to an increased LVMI and RWT in patients with hypertension (Table I). Comparison to previous studies The findings obtained in the current study are in line with previous data obtained by TDI in patients with congestive heart failure (CHF). Garcia et al 19 studied 110 patients with CHF and 68 controls using CDI and TDI. Patients with symptoms of CHF and preserved LVEF had a reduction in systolic longitudinal annular velocities. The authors concluded that impairment in LV systolic function is present even in patients with diastolic heart failure. Yu et al 20 and Yip et al 21 used echocardiography to demonstrate that myocardial systolic velocities were significantly lower in patients with heart failure and normal systolic LV function. Similar observations were made by the use of myocardial resonance imaging tagging; Palmon et al 22 showed that intramural circumferential and longitudinal myocardial shortening are depressed in hypertensive patients with LVH and normal global LV function. In addition, several studies analyzed midwall shortening to demonstrate that systolic dysfunction may be present among hypertensive patients, even when LVEF is normal. 23,24 These earlier data suggest that systolic dysfunction may develop in parallel to diastolic dysfunction in patients with still preserved global systolic LV function. It may also be that symptoms of CHF in these patients (until now attributed to isolated impaired relaxation) may partly result from deterioration of systolic function not detectable by conventional echocardiography. The present study is the first to report a difference in LV systolic function between healthy subjects and hypertensive subjects, using quantitative echocardiography. Further studies are needed to elucidate this condition of combined impairment of systolic function and diastolic function in patients with hypertension. These data render early identification and treatment of patients with hypertension even more important. Methodological considerations Echocardiography has been used successfully and with high reproducibility to detect LV diastolic dysfunction, most commonly with the use of CDI of the mitral inflow pattern. 5 However, the parameters measured by this method are not independent from loading conditions, such as preload and left atrial pressure. The most recent echocardiographic modality for the assessment of LV diastolic function is TDI. Several studies have shown that TDI is relatively preload-independent and quite sensitive to detect abnormalities of LV diastolic function. 25

5 American Heart Journal Volume 151, Number 6 Bountioukos et al 1323.e11 It is well known that quantification of LVEF using 2D echocardiography is strongly dependent on image quality and endocardial border delineation. Pulsed-wave TDI permits quantification of regional longitudinal myocardial systolic velocities with high temporal resolution and is feasible even in poor echocardiographic windows. Hence, pulsed-wave TDI allows evaluation of even minor changes in systolic LV function that are not detectable during 2D echocardiographic assessment of LV performance. Study limitations Several limitations need attention. First, most of the patients with hypertension used antihypertensive medication, which may have affected diastolic function and systolic function. Second, differences in loading conditions at the time of the echocardiographic evaluation still could have influenced the results, although the TDI results appear independent of loading conditions. Finally, the cutoff value to define normal systolic myocardial velocities is to some extent arbitrary because, currently, methodological and age-dependent variations have not permitted a universally accepted normal value to be defined. Conclusions Quantitative echocardiography using TDI reveals that patients with hypertension and preserved global LV systolic function frequently have combined impairment of systolic function and diastolic function. Further studies are needed to determine the clinical meaning of these observations. We thank Eleftheria Manola for secretarial assistance. References 1. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA 2005;294: Coresh J, Wei GL, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey ( ). 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