Influence of regression of left ventricular hypertrophy on left atrial size and function in patients with moderate hypertension

Abstract

Objectives. The aim of the study was to evaluate the effect of regression of left ventricular (LV) hypertrophy on left atrial (LA) size and function in patients treated with telmisartan, an angiotensin II receptor blocker. Methods. Patients population included 80 patients with mild–moderate LV hypertrophy treated with telmisartan. Patients were followed over a period of 12 months from the start of telmisartan treatment. LA size was measured during systole from the parasternal long‐axis view from M‐mode. Atrial function was assessed by Doppler‐echocardiography and the following parameters were measured: transmitral peak A velocity, atrial filling fraction, atrial ejection force (AEF), peak E velocity, deceleration time and isovolumic relaxation time, LA maximal and minimal volume, and LV cardiac mass index (LVMI). Results. All patients had an increased LVMI and decrease during follow‐up. LA dimensions were greater at baseline and reduced after 1 year of treatment. LA volume indexes maximal volume, minimal volume and P volume were reduced compared with baseline value (maximal volume from 35±5 to 32±5, p<0.05; minimal volumes from 14±2 to 10±4, p<0.05). AEF, a parameter of atrial systolic function, increased from 12±3 to 15±2.4 (p<0.01). The reduction of LA volumes correlate with reduction of LVMI (LA maximal volume and LVMI r = 0.45; p<0.01; LA minimal volume and LVMI r = 0.34; p<0.05). A positive correlation was also found between LV mass index and P volume (r = 0.41; p<0.01), LV mass index and LA active emptying volume (r = 0.39; p<0.01), and LV mass index and LA total emptying volume (r = 0.38; p<0.05). Conclusions. The present study suggests that regression of LV hypertrophy due to telmisartan is associated with reduction of LA volumes that expresses variation of LV end‐diastolic pressure. The reduction of LV end‐diastolic pressure is associated with an increase in diastolic filling and with a significant reduction of active and passive emptying contribution of left atrium to LV stroke volume.

• Angiotensin II receptor blocker
• diastolic dysfunction
• left atrial function
• left atrium
• left ventricular hypertrophy

Introduction

The left atrium (LA) is enlarged in hypertensive patients. The mechanism by which hypertension leads to LA enlargement seems related to hemodynamic changes. Systolic blood pressure (SBP) is a well‐established determinant of left ventricular (LV) mass in hypertension [1], [2] and LA size is significantly related to LV mass [3], [4]. A relation between SBP and LA enlargement has previously been reported in the Framingham Heart Study [5]. In this population, LA enlargement was associated both with the duration of elevated blood pressure and with the level of systolic pressure [5]. LA size reflects the chronicity and duration of LA hypertension and the severity of LV dysfunction [3]. It has been suggested that the LA enlarged asymmetrically; hence, LA volumes may be more accurate measures of atrial size. During diastole, the LA is directly exposed to pressures in left ventricle that increase with decreased LV compliance [6]. LA pressure increase to maintain adequate filling [7] and the increased atrial wall tension leads to chamber dilatation and stretching of the atrial myocardium [6].

The aim of the study was to evaluate the effect of regression of LV hypertrophy on LA size and function in patients with mild‐to‐moderate hypertension treated with telmisartan, an angiotensin II receptor blocker (ARB).

Methods

Study population

We screened 290 consecutive hypertensive patients with a SBP >140 mmHg and diastolic blood pressure (DBP) >90 mmHg. Of these, 120 were included in the study because they matched inclusion criteria, another 20 patients were excluded because they did not respond to monotherapy with telmisartan, 13 patients were excluded because of technically inadequate Doppler echocardiography studies of the pulmonary veins and seven patients did not complete the 1‐year follow‐up. Therefore, data were obtained from 80 patients (57 men and 23 women of mean age 53±10 years), with essential hypertension defined according to the Sixth Report of the Joint National Committee on detection, evaluation and treatment of high blood pressure [8]. The presumed duration of hypertension ranged from 1 to 5 years; patients were not taking any medication at the time of enrollment and 20 of them had been free of medication for the previous 3 months. All patients were in sinus rhythm. Exclusion criteria were: diabetes, supraventricular arrhythmias, mitral and aortic valvular diseases or prosthesis, clinical symptoms or signs of heart failure, known coronary artery disease, regional wall motion abnormalities or a global ejection fraction less than 50% on echocardiographic examinations [9].

Demographics and clinical characteristics of the patients are shown in Table I.

Table I. Demographic and clinical characteristics of patients at baseline.

	80 patients
Age (years)	53±10
Male/female	57/23
Height (cm)	170±14
Weight (kg)	86±17
Body mass index (kg/m^2)	26±3
Heart rate (beats/min)	77.6±12
Systolic blood pressure (mmHg)	157.5±5.1
Diastolic blood pressure (mmHg)	104.3±2.1
Interventricular septal thickness (cm)	1.21±0.17
Posterior wall thickness (cm)	1.08±0.10
Left ventricular mass (g)	230.8±46
Left ventricular end diastolic diameter (cm)	5.22±0.58
Ejection fraction (%)	61±8

The protocol was approved by the Ethical Committee of our University and all patients signed an informed consent form.

The starting dose of telmisartan was 40 mg. If the patient did not achieve the target blood pressure of <130/90 mmHg after 1 month of treatment, the dose was increased to 80 mg. No other antihypertensive agents were permitted during the course of the study. Patients took telmisartan once daily at 08.00 h, with the exception of the clinic visit days. Patients were followed over a period of 12 months from the start of telmisartan treatment.

Echocardiography

A complete mono‐ and two‐dimensional Color Doppler echocardiogram was performed on each patient using a commercial Hewlett Packard echocardiograph with a 2.5‐MHz mechanical probe.

LA function was assessed using the following parameters:

• Transmitral pulsed Doppler was recorded from the apical four‐chamber view, with the sample volume positioned between the tips of the mitral leaflets. Peak early filling (E) and atrial filling (A) velocities were recorded. Deceleration time and pressure half time was measured from the transmitral flow pattern.

• The atrial ejection force (AEF) was evaluated using the following equation [10], [11]:.

• Mitral orifice area was assumed to be circular and estimated from the mitral annulus diameter as measured from the apical four‐chamber view.

The following parameters were measured and compared:

• LA size was measured during systole along the parasternal long‐axis view from two‐dimensionally guided M‐mode tracing [12].

• LA volumes were measured from the apical four‐chamber and two‐chamber views by means of the biplane area–length method, and corrected for body surface area [12]. LA volumes were determined at mitral valve opening (maximal volume), at the onset of atrial systole (p wave of electrocardiogram, P volume), and at mitral valve closure (minimal volume). LA volumes were measured from the apical four‐chamber and two‐chamber views by means of the biplane area–length method, and corrected for body surface area [13]. From the LA volumes, the following parameters were estimated: LA passive emptying was assessed as: LA passive emptying volume (maximal volume−P volume), conduit volume [LV stroke volume−(Maximal volume−minimal volume)] and LA passive emptying fraction (LA passive emptying volume/maximal volume); LA active emptying was estimated using: LA active emptying volume (P volume−minimal volume) and LA active emptying fraction (LA active emptying volume/P volume); LA total emptying volume was also calculated (maximal volume−minimal volume); contribution of passive emptying volume [(maximal volume−P volume)/stroke volume], of conduit volume (conduit volume/stroke volume) and of active emptying volume [(P volume−minimal volume)/stroke volume] to LV stroke volume was also evaluated [14].

Patients with moderate and severe mitral regurgitation were excluded from the study. All Doppler results are the mean measurements of five cardiac cycles. The Doppler signal was analyzed using an IBM computer.

LV internal dimension, and septum and posterior wall thickness were measured according to the American Society of Echocardiography guidelines [12]. LV mean wall thickness was determined as the mean value of septum and posterior wall thickness at the end of diastole. Relative wall thickness was calculated as the ratio of 2×posterior wall thickness/LV end‐diastolic diameter. LV mass was calculated using the following equation:where LVEDD indicates LV end‐diastolic diameter, LVPWT LV posterior wall thickness and IVST interventricular septum thickness. The LV mass was normalized for body surface area to determine the LVMI (g/m²) [15].

LV hypertrophy was considered present when LV mass indexed for body surface area was >116 g/m² for men and >104 g/m² for women [15].

Transmitral pulsed Doppler was recorded from the apical four‐chamber view, with the sample volume positioned between the tips of the mitral leaflets. Peak early filling (E) and atrial filling (A) velocities were recorded. The deceleration time of peak E wave (dec t), the duration of the mitral A wave (MA dur) and isovolumic relaxation time (IVRT) were measured from the transmitral flow pattern [16].

The pulmonary venous flow velocity wave was analyzed for measurement of peak systolic (SPV) and diastolic (DPV) forward velocities, reversal wave peak flow velocity (PVA) and the duration of the reversal wave during atrial contraction (PA dur). In case of biphasic systolic flow, the maximal velocity was measured on the taller of the two peaks [17]. The ratio between pulmonary venous systolic and diastolic flow velocities (S/D) was calculated for a better evaluation of diastolic filling.

All Doppler results are the mean measurements of five cardiac cycles. The Doppler signal was analyzed using an IBM computer.

Serial echocardiography was performed at 1, 3, 6, 9 and 12 months, so that changes in LVMI (g/m²) and LV function could be related to changes in blood pressure.

Statistical analysis

Data are expressed as mean value±standard deviation for continuous variables. The statistical significance of serial changes in echocardiographic parameters was determined by one‐way analysis of variance for repeated measures. Bivariate correlations between LA size and variables of LV diastolic function were assessed with Pearson's correlation coefficients. Statistical software (SPSS Version 10.0 SPSS, Inc) was used for statistical analysis. A p‐value of <0.05 (two‐tailed) was considered significant.

Results

The clinical characteristics of patients are shown in Table I. Throughout the study, no change in doses and in the number of antihypertensive drugs occurred. Both SBP and DBP fell significantly after 3 months of telmisartan treatment; thereafter, there were further, smaller reductions in blood pressure (Table II). Six patients developed atrial fibrillation during the follow‐up; four of them had a spontaneous conversion of arrhythmia and two patients were cardioverted with amiodarone. LA dimensions were greater at baseline and reduced after 1 year of treatment. LV end‐diastolic and LV end‐systolic volumes did not change significantly after 1 year of treatment. Ejection fraction was also preserved (Table I). LA volume indexes maximal volume, minimal volume and P volume were reduced compared with baseline value (maximal volume from 35±5 to 32±5, p<0.05; minimal volumes from 14±2 to 10±4, p<0.05). LA passive emptying volume, LA active emptying volume and LA total emptying volume reduce after 1 year of treatment (Table III). LA passive emptying fraction, LA active emptying fraction, conduit volume and LA total emptying fraction did not change significantly. The reduction of LA volumes correlate with reduction of LV mass index (LA maximal volume and LV mass index r = 0.45; p<0.01; LA minimal volume and LVMI r = 0.34; p<0.05). A positive correlation was also found between LV mass index and P volume (r = 0.41; p<0.01), LV mass index and LA active emptying volume (r = 0.39; p<0.01), and LV mass index and LA total emptying volume (r = 0.38; p<0.05) (Table IV). Atrial function was evaluated by using combined analysis of transmitral flow (MF) pattern and pulmonary venous flow (PVF) pattern. AEF, a parameter of atrial systolic function, was also calculated and increased from 12±3 to 15±2.4 (p<0.01). At baseline, all patients had an abnormal relaxation pattern of MF. After 1 year of treatment, the prevalence of normal pattern was 21%. No patients developed a pseudonormal pattern. The reduction of LVMI was associated with an increased E/A ratio (from 0.59±0.2 to 0.88±0.2; p<0.01), shortened IVRT (from 114±14 to 105±13, p<0.01), decreased deceleration time (from 230±34 to 214±21 ms; p<0.01). At baseline, the pulmonary venous systolic fraction and the S/D ratio were increased and the deceleration time of the D wave was prolonged. The reduction of LV mass index was associated with a reduction of the deceleration time of D wave and to a reduction of S/D ratio. The regression of LV hypertrophy was also associated with the reduction of the difference in duration between reverse pulmonary venous and forward mitral A waves (from 26±6 to 7±0.8).

Table II. Serial evaluation of clinical and echocardiographic parameters during the follow‐up.

Parameters	Baseline	3 months	6 months	12 months
SBP (mmHg)	142.5±5.1	130.5±4.3**	129.9±4.2**	128±3.7 **
DBP (mmHg)	93.3±2.1	89±1.3 *	87.4±2.5 **	86.1±2.1**
HR (beats/min)	77.6±12	75±9	76±10	75±9
LVMI	120.8±7	118.9±5	116.8±7	109±3**
E velocity	0.46±0.15	0.48±0.1	0.50±0.19	0.60±0.2**
A velocity	0.77±0.25	0.73±0.20	0.70±0.18 *	0.68±0.17**
E/A	0.59±0.2	0.65±0.19	0.71±0.18*	0.88±0.2*
MA dur (ms)	150±21	150±19	149±21	148±18
Dec t	230±34	228±27	217±21*	214±21**§
IVRT	110 ± 14	108 ± 12	106 ± 8*	105 ± 13**
Syst PVF	44±11.8	48±10.9	50±10.6	50±10.3*
Diast PVF	38±9.9	40±11	43±10.6	45±9.3*
PVA	26 ± 7.9	22 ± 6.8*	22 ± 5.7*	22 ± 7.4*
PA dur (ms)	176±20	164±19**	159±22**	155±20**

SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; LVMI, left ventricular mass index; E, peak early filling; A, atrial filling (A); MA dur, the duration of the mitral A wave; Dec t, deceleration time of peak E wave; IVRT, isovolumic relaxation time; Syst PVF, peak systolic forward velocity; Diast PVF, peak diastolic forward velocity; PVA, reversal wave peak flow velocity; PA dur, duration of the reversal wave during atrial contraction.

*p<0.05; **p<0.001 vs baseline; §p<0.001 vs 3 months.

Table III. Serial evaluation of left atrial volumes during the follow‐up.

Parameters	Baseline	3 months	6 months	12 months
LA antero‐posterior diameter (mm)	39±7	39±6	38±5	36±6*
LA supero‐inferior diameter (mm)	42±6	40±4	40±5	38±6*
Maximal volume (cm^3)	35±5	34±6	34±4	32±5*
P atrial volume (cm^3)	18±3	16±5	15±5	12±6*
Minimal volume (cm^3)	14±2	12±3.1	11±2	10±4
Conduit volume (cm^3)	34±4	33±5	32±2	31±6
Passive emptying volume (cm^3)	17±3	18±3.2	19±3	20±2.6
Active emptying volume (cm^3)	4±0.4	4±0.6	4±0.7	2±0.4*

LA, left atrium.

*p<0.05.

Table IV. Pearson's correlation of echocardiographic parameters with left ventricular mass index.

Parameter	r	p
LA maximal volume	0.45	0.01
LA minimal volume	0.34	0.05
LA P atrial volume	0.41	0.01
LA active emptying volume	0.39	0.01
LA total emptying volume	0.38	0.05

LA, left atrium.

Discussion

The present study evaluated the effects of regression of LV hypertrophy on LV diastolic function and on LA size. LA size was significantly related to LV mass, in particularly LA enlargement was associated with eccentric LV hypertrophy in these patients with mild‐to‐moderate hypertension. The present study shows also that LA enlargement was associated with reduced diastolic LV function and that regression of LV hypertrophy induced a reduction of LA size and a recovery of diastolic dysfunction.

LA size, as measured by a single M‐mode dimension, is associated with the presence of cardiovascular disease and cardiovascular risk factors; i.e. hypertension [18]. The LA may not enlarge in a symmetrical fashion, and any or all three of its orthogonal axes may increase at rates greater than the others. Hence, the use of a single linear dimension may not accurately reflect either LA volume or its change [19]. Different methods have been proposed to measure LA volume: four‐chamber area–length and biplane Simpson; and more recently Pritchett and coworkers validated an elliptical model that incorporates two short‐axis and one long‐axis measurements [19–21]. In the present study, LA volumes were measured echocardiographically according to a biplane area–length method combining measures obtained from four‐chamber and two‐chamber apical views. We evaluated different LA volumes from the maximal to the minimal volume to assess the possible adaptive changes in LA mechanical function in hypertensive patients taking an ARB, telmisartan. In our population, LA size was associated with longer IVRT, higher E/A ratio and higher S/D ratio suggesting that both impaired relaxation and increased passive stiffness influence LA size. LA function is an important determinant of LV filling particularly when LV compliance is reduced [22]. At the end of follow‐up, the regression of diastolic dysfunction parameters was associated with a reduction of LA size. LA enlargement in hypertensive patients could be secondary both to changes in systolic and diastolic function. It is well established that the LA reservoir and pump function are increased in hypertensive patients with impaired LV relaxation [23]. The LA reservoir volume during ventricular systole could compensate for the impaired early LV filling. In the present study, both the contributions from LA passive and active emptying volumes to LV stroke volume increased after reduction of LV hypertrophy and normalization of LV diastolic parameters. The conduit volume remained unchanged. Reduction of LA passive and active emptying fractions suggests that LA functions tend to normalize after reduction of LV hypertrophy.

LA pressure has been shown to have a negative correlation with pulmonary venous systolic fraction and S/D ratio in patients with pseudonormal mitral inflow pattern [24] The difference between PVA reversal wave duration correlate with an increase in LV pressure during atrial contraction and LV end‐diastolic pressure [17], [25]. A longer duration of the pulmonary venous A wave than that of the mitral valve predicted an LV end‐diastolic pressure >15 mmHg [17].

The increase of LV end‐diastolic pressure caused an increase in the duration of the reversal wave of pulmonary venous flow occurring during atrial contraction. We reported this compensatory mechanism in many of our patients. The regression of LV hypertrophy determined a better LV filling performance and was associated with a reduction of PA duration.

Study limitation

LA overload was derived using atrial volumes, although an invasive measure of LA pressure would be more accurate. We only investigated patients responding to telmisartan and this may have influenced the results. Is it possible that the results depend on a direct effect of the ARB.

Conclusions

Results from the present study suggest that regression of LV hypertrophy related to telmisartan, an ARB, is associated with modification of LA volumes that express variation of LV end‐diastolic pressure. The reduction of LV end‐diastolic pressure is associated with significant improvement of diastolic filling parameters related to active relaxation and passive chamber stiffness. Echocardiographic evaluation of LA maximal and minimal volumes can help for a better evaluation of diastolic dysfunction of LV.