Journal of Human Hypertension (2004) 18, 397–402 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Association of left with left ventricular structure and function in hypertensive patients with left : the LIFE study

ZB Li1, K Wachtell2, PM Okin1, E Gerdts3, JE Liu1, MS Nieminen4, S Jern5, B Dahlo¨f5 and RB Devereux1 1Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA; 2Department of Medicine, Glostrup University Hospital, Glostrup, Denmark; 3Haukeland University Hospital, Bergen, Norway; 4Department of , Helsinki University Central Hospital, Helsinki, Finland; 5Sahlgrenska University Hospital/O¨stra, Gothenburg, Sweden

Electrocardiographic (ECG) left bundle branch block tion (56710 vs 6178%), midwall shortening (1472 vs (LBBB) is associated with left ventricular hypertrophy 1672%), stress-corrected midwall shortening (90713 vs (LVH), but its relation to left ventricular (LV) geometry 97713%) (all Po0.001), and lower LV stroke index and function in hypertensive patients with ECG LVH is (3877 vs 4279 ml/m2)(Po0.05). Patients with LBBB unknown. Echocardiograms were performed in 933 also had reduced LV inferior wall and lower mitral E/A patients (548 women, mean age 6677 years) with ratio (0.7570.18 vs 0.8770.38) (all Po0.05). The above essential hypertension and LVH by baseline ECG in univariate results were confirmed by multivariate ana- the Losartan Intervention For Endpoint reduction in lyses adjusted for gender, age, blood pressures, height, hypertension (LIFE) study. LBBB, defined by Minnesota weight, body mass index, rate, and LV mass index. code 7.1, was present in 47 patients and absent in 886 Among hypertensive patients at high risk because of patients. Patients with and without LBBB were similar in ECG LVH, the presence of LBBB identifies individuals age, gender, body mass index, blood pressure, pre- with worse global and regional LV systolic function and valence of diabetes, and history of myocardial infarc- impaired LV relaxation without more severe LVH by tion. Despite similarly elevated mean LV mass (126725 echocardiography. vs 124726 g/m2) and relative wall thickness (0.4170.07 Journal of Human Hypertension (2004) 18, 397–402. vs 0.4170.07, P ¼ NS), patients with LBBB had lower LV doi:10.1038/sj.jhh.1001709 fractional shortening (3076 vs 3476%), ejection frac- Published online 8 April 2004

Keywords: echocardiography; electrocardiogram; hypertrophy; left bundle branch block; left

Introduction The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a prospective trial Electrocardiographic (ECG) left bundle branch block to compare the efficacy of losartan vs atenolol-based (LBBB) is associated with left ventricular hypertro- 1 treatment in reducing the rate of cardiovascular phy (LVH). Several studies have shown associa- morbidity and mortality in hypertensive patients. tions between LBBB and left ventricle systolic and The LIFE study enrolled patients with essential diastolic dysfunction in otherwise healthy indivi- 4,5 2,3 hypertension and ECG-defined LVH. The current duals. However, it is unknown whether LBBB is study was undertaken to evaluate the association of associated with additional LV geometric and func- LBBB with LV geometric and functional abnormal- tional abnormalities in hypertensive patients with ities in patients with hypertension and ECG LVH ECG-defined LVH. enrolled in the LIFE echocardiography substudy.

Correspondence: Dr RB Devereux, Weill Medical College of Cornell University, Division of Cardiology, Box 222, 525 East Methods 68th Street, New York, NY 10021, USA. E-mail: rbdevere@ med.cornell.edu Subjects This study was supported by Grant COZ 368 from Merck & Co., Inc., West Point, PA, USA. Drs. Devereux and Dahlo¨f receive All subjects in this study were from the LIFE 6 occasional honoraria from Merck. echocardiography substudy. The LIFE echo sub- Published online 8 April 2004 study was undertaken to evaluate the effects of Left bundle branch block and LV function ZB Li et al 398 losartan- vs atenolol-based treatment on LV geome- VCRs and digitizing tablet and monitor screen try and function in a subset of 960 patients (mean overlay for calibration and performance of each age 66 years (range 55–81)) with systemic hyperten- measurement.8–10 Linear LV internal dimension and sion (arterial pressure 160–200/95–115 mmHg after interventricular septal and posterior wall thickness placebo run-in) and ECG LVH, constituting 11% of were measured at end-diastole and end-systole the entire LIFE population.5,6 The patient exclusion according to American Society of Echocardiography criteria of the LIFE study included certain cardio- recommendations.11,12 Left atrial end-systolic di- vascular conditions and noncardiac diseases that mension was measured from the trailing edge of might have limited long-term survival of the patient, the posterior aortic–anterior left atrial complex to or increase the likelihood of nonadherence to study avoid erroneously including the variable size of the medication.5,6 All participants in this study had connective tissue-filled space between these struc- baseline and follow-up ECGs and echocardiograms. tures in atrial size.13 The aortic annular and root The ECG diagnostic criteria for LVH were Cornell diameter were measured at end-diastole using the voltage  QRS duration X2440 mV  ms or modified same method as in previously published papers.14,15 Sokolow–Lyon criteria SV1 þ RV5/RV6438 mV.5,6 Pulse-wave Doppler recordings of transmitral flow LBBB was defined according to the standard ECG velocities were obtained by placing the sample criteria of Minnesota code 7.1 as follows: QRS volume between the tips of the mitral leaflets. duration 0.12 s or greater in I, II, and III, and R-peak Transmitral flow measurements included peak early duration 0.06 s or more in any of I, II, aVL, V5, or V6. LV filling velocity (E-wave), peak atrial filling The current study included all (n ¼ 933) patients velocity (A-wave), and their ratio (E/A ratio); and having both the needed ECG results and echocardio- the deceleration time and pressure half-time of early graphic LV structural and functional parameters. diastolic transmitral flow (E-wave). Pulse-wave The characteristics of the study population are Doppler recordings of isovolumic relaxation time shown in Table 1. (IVRT) were obtained by placing the sample volume between the anterior mitral leaflet and LV outflow Echocardiographic methods and performance tract from the closure spike of the to 16 protocol onset of the mitral flow. Pulse-wave Doppler recordings of the left ventricular outflow tract Echocardiograms were performed in 47 selected (LVOT) velocity were obtained by placing the echocardiography centres in Denmark, Finland, Ice- sample volume at the level of aortic annulus, and land, Norway, Sweden, the United Kingdom, and the the LVOT velocity Doppler spectral patterns were United States using high-quality commercially avail- traced electronically to measure the time–velocity able echocardiographs with 3.0. to 3.5 and 2.0 to 2.5 integral (TVI) of LVOT; the latter was multiplied by MHz probes and VHS or Super-VHS video recorders. the calculated aortic annular cross-sectional area, Echocardiographic methods and performance proto- which is defined as p  (LVOT radius)2 to derive LV col were based on procedures used as in previous stroke volume. Cardiac output was calculated as studies7,8 and have been described in detail.6,9,10 The stroke volume  heart rate.17,18 Heart rates were echocardiograms were sent to Cornell Medical measured at the same time from Doppler spectral Center in New York City for blinded interpretation recordings. Measurements of two to three cardiac by experienced physicians, and blinded verification, cycles were averaged. and correction of measurements if necessary, by highly experienced investigators. Calculation of derived variables Echocardiographic measurements From echocardiographic end-diastolic LV dimen- The measurements were made blindly using com- sions, LV mass was calculated by an anatomically validated formula (r ¼ 0.90)19 with good inter-study puterized review stations (Digisonics, Inc., Houston, 20 TX, USA) equipped with NTSC or PAL standard reproducibility (r ¼ 0.93). LV mass index was calculated as the ratio LV mass/body surface area. Relative wall thickness was calculated as diastolic Table 1 Patient characteristics (n ¼ 933) posterior LV wall thickness/LV internal radius.21 LVH was defined by LV mass index 4116 g/m2 in 7 Age (years) 66 7 men or 4104 g/m2 in women.7 Increased relative Women (%) 59 Height (cm) 169.479.7 wall thickness was defined by relative wall thick- 22 Weight (kg) 78.3713.8 ness 40.43, the 97.5 percentile in normal subjects. Body surface area (m2) 1.970.19 Normal LV geometry was identified when LV mass Body mass index (kg/m2) 27.374.7 index and relative wall thickness were both normal. Heart rate (bpm) 67.5711.8 Clinic systolic blood pressure (mmHg) 173.8721.1 Concentric LVH was defined by abnormally in- Clinic diastolic blood pressure (mmHg) 95.5711.9 creased values for both LV mass index and relative wall thickness. Eccentric LV hypertrophy was Data are expressed as mean7s.d. unless otherwise noted. defined by abnormally increased LV mass index

Journal of Human Hypertension Left bundle branch block and LV function ZB Li et al 399 with normal relative wall thickness. Concentric LV meters were also further confirmed by multivariate remodelling was present when abnormally in- analyses controlling for gender, age, blood pres- creased relative wall thickness coexisted with sures, height, weight, body mass index, heart rate, normal LV mass index.23 and LV mass index as covariates. Two-tailed Po0.05 LV systolic fractional shortening, ejection fraction, was considered statistically significant. and circumferential end-systolic wall stress (ESS) were calculated by standard methods.24,25 Stroke volume from linear LV dimensions was calculated as the difference between LV end-diastolic and Results end-systolic volume by the method of Teichholz Patient characteristics et al26 and was used to calculate LVejection fraction. The ejection fraction was also calculated from the The clinical characteristics of the 47 patients with wall motion scores of all LV wall segments. Ejection LBBB and 886 patients without LBBB are shown in fractions from both LV linear dimension and two- Table 2. The LBBB group patients included more dimensional wall motion scores have been shown to women, and who were slightly older and had predict prognosis in a population-based sample.27 slightly higher systolic and diastolic blood pressures and wider pulse pressure. However, none of the differences between patient groups with and with- Echocardiographic evaluation of LV function out LBBB, except with regard to gender were statistically significant. Both groups had similar Global LV systolic function was accessed by frac- prevalence of diabetes and history of myocardial tional shortening, ejection fraction, and cardiac infarction. output. Regional LV wall motion was assessed based on motion and thickening of individual LV wall segments. In this study, the LV was divided into 14 segments at basal, midcavity, and apical LV level, LV mass and geometry respectively.28 Based on the motion and thickening of each segment, wall motion was scored on a Comparisons of LV structural characteristics be- scale from normal to dyskinetic. To derive an tween groups with and without LBBB are shown estimate of overall LV ejection fraction from in Table 3. All patients had similar diastolic regional wall motion score, the following score interventricular septal and posterior wall thick- values were assigned to each segment: normal nesses and LV internal dimension. Both groups also motion ¼ 4.5, mildly hypokinetic ¼ 3.5, moderately had similarly elevated mean LV mass, LV mass index hypokinetic ¼ 2.5, severely hypokinetic ¼ 1.5, (LV mass/BSA), and relative wall thickness. As a akinetic ¼ 0, and dyskinetic ¼À1.0. result, eccentric or concentric LVH or concentric LV Diastolic LV filling function was evaluated by the remodelling occurred in 40.4, 34.0, and 4.3%, following Doppler parameters: peak E-wave velo- respectively, of patients with LBBB, and in 46.3, city, peak A-wave velocity, E/A ratio, E-wave 25.0, and 9.3%, respectively, of patients without deceleration time, and IVRT. E/A ratio o1 was LBBB. The LV geometric and LV mass differences considered low in the age group of LIFE study.10 E- between patients with and without LBBB groups wave deceleration time o150 ms was considered were not statistically significant. abnormally short29 and 4250 ms was considered abnormally prolonged.30 IVRT 4100 ms was con- sidered pathologic.16,30 LV diastolic function was Table 2 Clinical characteristics of patients with and without left considered to be normal when E/A ratio, E-wave bundle branch block deceleration time, and IVRT were all within normal No LBBB LBBB P-value ranges. (n ¼ 886) (n ¼ 47)

Gender (% female) 53 59 o0.01 Statistical analysis Age (years) 66.377.0 67.776.8 NS Height (cm) 169.5710 167.979.4 NS SPSS statistical software version 11.0 (SPSS, Inc., Weight (kg) 78.5713.9 75.2711.6 NS Chicago, IL, USA) was used for data analysis. Body mass index (kg/m2) 27.474.7 26.773.8 NS Results were presented as mean7s.d. LV geometric Clinic systolic blood 174.0721.2 171.7718.1 NS pressure (mmHg) measurements, Doppler parameters, and derived Clinic diastolic blood 95.6712.0 92.9710.0 NS variables were compared between patient groups pressure (mmHg) with and without LBBB by independent samples t- Heart rate (bpm) 67712 71712 NS test, and the results were further confirmed by History of diabetes (%) 13.1% 11.3% NS History of myocardial 4.3% 3.0% NS nonparametric two samples test. The significance of infarction (%) difference between categorical variables was ac- 2 cessed by Pearson’s w test. Univariate analysis LBBB ¼ left bundle branch block, NS ¼ not significant. results for LV systolic and diastolic function para- Data are expressed as mean7s.d. unless otherwise noted.

Journal of Human Hypertension Left bundle branch block and LV function ZB Li et al 400 LV systolic function Table 6. The patient group with LBBB had lower peak E velocity, higher mitral valve The comparisons of LV global and regional peak A velocity, lower mitral valve E/A ratio, and systolic function parameters between patients longer mitral annulus E-wave deceleration time and with and without LBBB are presented in Tables 4 isovolumetric relaxation time than the patient group and 5, respectively. Compared to the group without without LBBB. The difference in mitral annulus E/A LBBB, the LBBB group had significantly lower ratio between two groups was statistically signifi- LV global systolic function indices, including frac- cant (Po0.05). tional shortening, ejection fraction from linear LV dimension, midwall shortening, and stress- corrected midwall shortening (all Po0.001), as Table 5 LV systolic wall motion score in patients with and well as lower ejection fraction derived from without LBBB two-dimensional wall motion scores, lower cardiac index, and lower LV stroke volume No LBBB LBBB P-value (all Po0.05) (see Figure 1). The LBBB group (n ¼ 724) (n ¼ 33) also had worse LV regional wall systolic function 7 7 indicated by lower LV wall motion score of all LV Anterior septum 1.6 1.8 2.7 2.9 o0.05 Inferior septum 1.571.6 2.472.4 o0.05 wall segments. The wall motion scores of the Inferior wall 1.571.6 2.172.4 o0.05 anterior and inferior interventricular septum and Lateral wall 1.471.6 1.972.3 NS the inferior LV wall were significantly lower in the LBBB group than in the group without LBBB LV ¼ Left ventricular, LBBB ¼ left bundle branch block, NS ¼ not significant. (Po0.05). Data are expressed as mean7s.d.

LV diastolic function 100 No LBBB Comparisons of LV diastolic parameters between 90 groups with and without LBBB are presented in With LBBB 80 70 Table 3 LV structural features in patients with and without LBBB 60 No LBBB LBBB P-value (n ¼ 886) (n ¼ 47) 50 40 IVSD (cm) 1.1670.16 1.1570.12 NS LVID (cm) 5.2970.57 5.3170.64 NS 30 7 7 PWTD (cm) 1.07 0.13 1.07 0.09 NS 20 LV mass (g) 234.1756.6 232.72753.6 NS LV mass/BSA (g/m2) 123.6725.8 125.96725.0 NS 10 RWTD 0.4170.1 0.4170.1 NS 0 Fractional Ejection Ejection Midwall Stress-corrected BSA ¼ body surface area, IVSD ¼ interventricular septum thickness in shortening (%) fraction from fraction from shortening (%) midwall diastole, LBBB ¼ left bundle branch block, LV ¼ left ventricular, LV linear wall motion shortening (%) LVID ¼ left ventricular internal dimension in diastole, NS ¼ not dimensions(%) scscore (%) significant, PWTD ¼ left ventricular posterior wall thickness in diastole, RWTD ¼ relative wall thickness in diastole. Figure 1 LV global systolic function in patients with and without Data are expressed as mean 7s.d. LBBB. All Po0.05.

Table 4 LV global systolic function in patients with and without LBBB

No LBBB LBBB P-value (n ¼ 886) (n ¼ 47)

Fractional shortening (%) 33.575.7 30.076.4 o0.001 Ejection fraction by 2D/M-mode from Teichholz (%) 61.478.2 56.379.8 o0.001 Ejection fraction from wall motion score sum (%) 61.5374.9 59.077.5 o0.05 Midwall shortening (%) 15.572.1 14.272.3 o0.001 Stress-corrected midwall shortening (%) 97.2713.0 90.4712.5 o0.001 Pulse pressure/stroke volume (mmHg/ml) 1.170.3 1.270.3 o0.05 Stroke volume by Doppler (ml) 78.4717 70.5713 o0.05 Stroke volume by 2D/M-mode from Teichholz (ml) 82.3716 76.0717 o0.05

LV ¼ Left ventricular, LBBB ¼ left bundle branch block, NS ¼ not significant. Data are expressed as mean7s.d. Note: The above univariate analyses were confirmed by multivariate analyses that yield the same statistical significance after controlling for gender, age, blood pressures, height, weight, body mass index, heart rate, and LV mass index as covariates.

Journal of Human Hypertension Left bundle branch block and LV function ZB Li et al 401 Table 6 LV diastolic function in patients with and without LBBB

No LBBB LBBB P-value (n ¼ 763) (n ¼ 38)

Mitral valve peak E velocity (cm/min) 65.9718.3 64.0716.1 NS Mitral valve peak A velocity (cm/min) 66.6719.1 80.9722.6 NS Mitral valve E/A max 0.970.4 0.870.2 NS Mitral annulus E/A max 0.870.3 0.770.2 o0.05 Mitral valve deceleration time (ms) 216.3764.5 221.8778.1 NS IVRT (ms) 114.6722.7 118.1729.9 NS

LV ¼ Left ventricular, IVRT ¼isovolumetric relaxation time, LBBB ¼ left bundle branch block, NS ¼ not significant. Data are expressed as mean7s.d. Note: The above univariate analyses were confirmed by multivariate analyses that yield the same statistical significance after controlling for gender, age, blood pressures, height, weight, body mass index, heart rate, and LV mass index as covariates.

Discussion E/A ratio of the LBBB patient group was statistically significantly lower than that of the patients without The present study clarifies the cardiac features LBBB (P ¼ 0.01). In multiple linear regression ana- associated with LBBB among hypertensive patients lysis with LBBB as indicator variable, together with with ECG LVH. This study had three main findings. relevant covariates (age, height, weight, systolic and First, the degree of anatomic LVH as derived by diastolic blood pressure, and body mass index), the direct echocardiographic measurements was vir- presence of LBBB was independently associated tually identical in patients with or without LBBB. with lower mean mitral E/A ratio than in patients Thus, the ECG criteria used to identify LVH in LIFE without LBBB (P 0.05). The differences in IVRT X o study (Cornell voltage QRS duration 2440 mV Â and E-wave deceleration time between patients with ms or modified Sokolow–Lyon criteria SV1 þ RV5/ and without LBBB were not statistically significant RV6 438 mV) were equally applicable to patients in either univariate analyses or in multivariate with or without LBBB. Second, despite the lack of analyses with the above covariates. One explanation differences between groups in severity of LVH or in could be that the indicators of LV diastolic function the level of blood pressure or the prevalence of used in this study were not as sensitive and specific diabetes or overt cardiovascular diseases, patients as some newer techniques, such as colour flow with LBBB had significantly lower indices of LV propagation and Doppler tissue imaging, to identify global systolic function, due in part to regional subtle changes in LV filling.34 dysfunction of the interventricular septum and LV inferior wall. Finally, patients with LBBB also showed a tendency to worse early diastolic LV Conclusions relaxation compared to patients without LBBB. Abnormal interventricular septal motion has been The present study identifies a strong association reported in LBBB patients without hypertension and between LBBB and LV systolic dysfunction in ECG LVH.3,31–33 In the current study, the echocardio- hypertensive patients with ECG LVH, despite lack graphic appearance of the interventricular septum of differences between patient groups with and again showed the characteristic asynchronous mo- without LBBB in clinical characteristics, degree of tion pattern and decreased motion magnitude. The echocardiographic LVH, or presence of coexisting wall motion score of the inferior LV wall was diseases. Among hypertensive patients at high risk significantly lower in LBBB patients compared to because of ECG LVH, the presence of LBBB identifies those without LBBB. The asynchronic contraction individuals with significantly worse LV global and and reduced motion of the interventricular septum regional systolic function and evidence of impaired and inferior LV wall are considered to be the major LV relaxation, who may thereby be likely to have an contributors to the lower indices of global LV systolic especially high rate of clinical events. function in hypertensive patients with ECG LVH and LBBB. In addition, the resemblance between these Acknowledgements findings and those of patients with dilated cardio- myopathy suggests that hypertensive patients with We thank Paulette A Lyle for assistance with ECG LVH who have LBBB, may be at increased risk preparation of the manuscript. of developing consequent . The current study also showed that the LBBB group patients had more impaired LV diastolic References function. The LBBB group showed lower peak 1 Sundstrom J, Lind L, Andren B, Lithell H. Left E-wave peak velocity, higher A-wave peak velocity, ventricular geometry and function are related to lower mitral valve E/A ratio, and longer IVRT and electrocardiographic characteristics and diagnoses. E-wave deceleration time. The mean mitral annulus Clin Physiol 1998; 18: 463–470.

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