Download Changes in left ventricular filling and left atrial function six

Journal of the American College of Cardiology
© 1999 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 34, No. 4, 1999
ISSN 0735-1097/99/$20.00
PII S0735-1097(99)00341-1
Changes in Left Ventricular Filling
and Left Atrial Function Six Months After
Nonsurgical Septal Reduction Therapy
for Hypertrophic Obstructive Cardiomyopathy
Sherif F. Nagueh, MD, FACC, Nasser M. Lakkis, MD, FACC, Katherine J. Middleton, RCT,
Donna Killip, RN, William A. Zoghbi, MD, FACC, Miguel A. Quiñones, MD, FACC,
William H. Spencer III, MD, FACC
Houston, Texas
OBJECTIVES
The purpose of this study was to evaluate changes in left ventricular (LV) filling, left atrial
(LA) volumes and function six months after nonsurgical septal reduction therapy (NSRT) for
hypertrophic obstructive cardiomyopathy (HOCM).
BACKGROUND Patients with HOCM frequently have enlarged left atria, which predisposes them to atrial
fibrillation. Nonsurgical septal reduction therapy results in significant reduction in left
ventricular outflow tract (LVOT) obstruction and symptomatic improvement. However, its
effect on LV passive filling volume, LA volumes and function is not yet known.
METHODS
Thirty patients with HOCM underwent treadmill exercise testing as well as 2-dimensional
and Doppler echocardiography before and six months after NSRT. Data included clinical
status, exercise duration, LVOT gradient, mitral regurgitant (MR) volume, LV pre-A
pressure and LA volumes. Left atrial ejection force and kinetic energy (KE) were computed
noninvasively and were compared with 12 age-matched, normal subjects.
RESULTS
New York Heart Association (NYHA) class was lower and exercise duration was longer (p ⬍
0.05) six months after NSRT. The LVOT gradient, MR volume and LV pre-A pressure were
all significantly reduced. HOCM patients had larger atria, which had a higher ejection force
and KE, compared with normal subjects (p ⬍ 0.01). After NSRT, LV passive filling volume
increased (p ⬍ 0.01), whereas LA volumes, ejection force and KE decreased (p ⬍ 0.01).
Reduction in LA maximal volume was positively related to changes in LV pre-A pressure (r ⫽
0.8, p ⬍ 0.05) and MR volume (0.4, p ⬍ 0.05). Changes in LA ejection force were positively
related to changes in LA pre-A volume (r ⫽ 0.7, p ⬍ 0.01) and KE (r ⫽ 0.81, p ⬍ 0.01).
The increase in exercise duration paralleled the increase in LV passive filling volume (r ⫽
0.85, p ⬍ 0.05).
CONCLUSIONS Nonsurgical septal reduction therapy results in an increase in LV passive filling volume and
a reduction in LA size, ejection force and KE. (J Am Coll Cardiol 1999;34:1123– 8) © 1999
by the American College of Cardiology
Nonsurgical septal reduction therapy (NSRT) is a promising new treatment for hypertrophic obstructive cardiomyopathy (HOCM) that has been shown to improve both
symptoms and exercise tolerance in patients with left ventricular outflow tract (LVOT) obstruction (1– 4). We have
also recently observed an improvement in left ventricular
(LV) diastolic dysfunction (pre-A pressure, tau and LV
compliance) after NSRT, which accounted for some of the
From the Cardiology Section, Department of Medicine, Baylor College of
Medicine, Houston, Texas. Supported by grants from the T.L.L. Temple Foundation, Lufkin; Dunn Foundation; and Methodist Hospital Foundation, Houston,
Texas.
Manuscript received December 31, 1998; revised manuscript received March 31,
1999, accepted June 23, 1999.
improvement in symptoms and exercise tolerance, six
months after the procedure (5). However, it is currently
unknown what effects NSRT has on LV filling and left
atrial (LA) size and function. The purpose of this study was,
therefore, to evaluate these changes.
METHODS
The protocol was approved by the institutional review board
of Methodist Hospital and Baylor College of Medicine, and
all patients gave written informed consent before participation. The group comprised 30 HOCM patients enrolled for
ethanol septal reduction therapy (4). Patients had asymmetric septal hypertrophy with septal thickness ⱖ1.5 cm, and
1124
Nagueh et al.
LV Filling and LA Size and Function After NSRT
Abbreviations and Acronyms
HCM ⫽ hypertrophic cardiomyopathy
HOCM ⫽ hypertrophic obstructive cardiomyopathy
KE
⫽ kinetic energy
LA
⫽ left atrial
LV
⫽ left ventricular
LVOT ⫽ left ventricular outflow tract
MR
⫽ mitral regurgitant
NSRT ⫽ nonsurgical septal reduction therapy
NYHA ⫽ New York Heart Association
RVOT ⫽ right ventricular outflow tract
TD
⫽ tissue Doppler
septum/posterior wall thickness ⱖ1.3. All patients had a
dynamic LVOT gradient ⱖ40 mm Hg at rest or
ⱖ60 mm Hg during dobutamine (at baseline) (3 patients).
Patients underwent treadmill exercise testing (Bruce protocol) at baseline and six months.
A group of 12 normal age-matched adults (mean age:
53 ⫾ 16 years; 7 women) served as control subjects, for the
purpose of comparing LA volumes and function. None of
these individuals had evidence of cardiovascular disease by
clinical and echocardiographic assessment. In addition, they
were not receiving medications.
Echocardiographic studies. Patients were imaged with an
Acuson XP-128 or a Hewlett-Packard Sonos 2000 ultrasound system equipped with a multifrequency transducer
(2.5 and 3.5 MHz) and tissue Doppler (TD) program.
Parasternal and apical views (four- and two-chamber) were
acquired first. Depth and gain settings were optimized to
allow recording of LA volumes. Right ventricular outflow
tract (RVOT) diameter in systole was measured in the
parasternal short axis view at the base of the heart, with
subsequent acquisition of systolic flow through the RVOT
using pulse Doppler. From the four-chamber apical view,
the sample volume was placed at mitral valve annulus then
at tips, and 5 to 10 cardiac cycles were recorded with pulse
Doppler at each site during normal respiration. With color
Doppler guidance, the LVOT gradient was recorded with
continuous-wave Doppler (6). Tissue Doppler program was
applied in pulse-wave mode (⫺30 to 30 cm/s) with gains
adjusted to minimize background noise. From the fourchamber view, a 5-mm sample volume was placed at the
lateral border of the mitral annulus (7) for recording 5 to 10
cycles. Studies were stored on 1⁄2-inch VHS videotape for
later playback and analysis.
Echocardiographic analysis. All measurements were performed by an observer blinded to clinical data on an off line
station equipped with 2-dimensional (2-D) and Doppler
analysis software (Digisonics 500). Using frame-by-frame
analysis, LA volumes were calculated at several points
during the cardiac cycle, with the method of multiple discs
(8). The following volumes were measured: maximal LA
volume (LA max., taken before mitral valve opening), atrial
JACC Vol. 34, No. 4, 1999
October 1999:1123–8
volume just before atrial contraction (LA pre-A) and
minimal left atrial volume (LA min., measured after atrial
contraction). Left atrial stroke volume was calculated as the
difference between LA pre-A and LA min. volumes. The
LV passive filling volume (rapid and mid-diastolic LV
filling) was computed as the difference between LA max.
volume and LA pre-A volume.
The mitral annulus diastolic diameter was measured in
the apical views, and mitral annulus area was then derived
(9). Subsequently, LA ejection force was calculated using
the equation: 0.5 ⫻ 1.06 ⫻ mitral annulus area ⫻ (peak A
velocity2) in kdyne (10). Left atrial kinetic energy was
calculated using the equation: 0.5 ⫻ 1.06 ⫻ LA stroke
volume ⫻ (A velocity2) in kerg (11). In the calculation of
LA kinetic energy, the absolute A velocity (peak A ⫺
velocity at onset of A) was used when this velocity did not
start from baseline (11). Mitral regurgitant (MR) volume
was derived as the difference between diastolic mitral inflow
(area of mitral annulus ⫻ velocity time integral of mitral
annular flow) and pulmonic outflow (RVOT area ⫻ velocity
time integral of RVOT systolic flow) (9). Peak LVOT
gradient was derived with the modified Bernoulli equation
as: LVOT gradient ⫽ 4v2, where v ⫽ peak velocity in
LVOT by continuous-wave Doppler (6). Left ventricular
pre-A pressure, which relates well to and has the same
Doppler correlates as the pulmonary capillary wedge pressure (12), was estimated using the equation LV pre-A
pressure ⫽ 3.2 ⫹ [1.1(E/Ea)], where Ea is the annular early
diastolic velocity at the mitral annulus lateral corner (13).
All echocardiographic measurements were ascertained at
baseline and six months.
Statistics. Data are presented as mean ⫾ SD. Unpaired t
testing was used to compare LA size and function between
the normal group and HOCM patients. Paired t testing was
applied in the evaluation of LA changes in size and function
six months after NSRT. Regression (linear or nonlinear)
analysis was used to relate changes in LA volumes, ejection
force, kinetic energy (KE), exercise duration, LVOT gradient, MR volume and LV pre-A pressure to one another.
Significance was set at a p value ⱕ 0.05.
RESULTS
Mean age was 53 ⫾ 15 (range 29 to 83) years (14 women).
At baseline before NSRT, 5 patients were in New York
Heart Association (NYHA) class IV with 21 patients in
class III, and 4 patients in class II (patients in class II could
not tolerate maximum medications) despite maximal medical therapy. All but three patients had a resting LVOT
gradient (52 ⫾ 33 [20 to 120] mm Hg, three had
dobutamine-provocable gradients). Patients had hyperdynamic ventricles, with 23 patients having mild, and 7
patients having moderate, mitral regurgitation (as assessed
by pulse Doppler of mitral inflow and RVOT outflow).
Satisfactory 2-D apical views, pulse Doppler of mitral
JACC Vol. 34, No. 4, 1999
October 1999:1123–8
Nagueh et al.
LV Filling and LA Size and Function After NSRT
1125
Table 1. Left Atrial Volumes, Ejection Force and Kinetic
Energy in HCM Patients Before and Six Months After NSRT
HCM at
Baseline
LA max. volume (ml)
LA min. volume (ml)
LA pre-A volume (ml)
LV passive filling
volume (ml)
LA stroke volume (ml)
LA ejection force
(kdyne)
LA kinetic energy
(kerg)
Figure 1. Left atrial (LA) stroke volume (SV) in the control group,
and in the HOCM group pre- and post-NSRT (comparing
controls with HOCM patients pre-NSRT: p ⬍ 0.001, 95%
confidence intervals for difference of means: 10 –22; comparing
controls with HOCM patients post-NSRT: p ⬍ 0.001, 95%
confidence intervals: 4.1–14.4).
inflow and RVOT as well as TD of mitral annulus were
obtained in all patients.
Changes in functional status, MR volume and pre-A
pressure six months after NSRT. After NSRT, patients
experienced a significant improvement in symptoms. Five
patients were in NYHA class II, 24 in class I and 1 in class
III (p ⬍ 0.01). Exercise tolerance was improved, with
exercise duration increasing from 270 ⫾ 147 to 412 ⫾ 177 s
(p ⬍ 0.05). The LVOT gradient was significantly lower at
six months (52 ⫾ 33 to 9 ⫾ 19 mm Hg, p ⬍ 0.01). The MR
severity was likewise reduced after the procedure, with 20
patients having none or trivial MR and 10 patients having
mild MR (23 patients had mild MR, and 7 patients had
moderate MR before NSRT). The MR volume decreased
from 16 ⫾ 12 ml before to 8 ⫾ 8 ml after NSRT (p ⬍ 0.05).
Also, the LV filling pressures were significantly lower (19 ⫾
6 to 14 ⫾ 5 mm Hg, p ⬍ 0.05).
HCM
Six Months
Post-NSRT
89 ⫾ 36
34 ⫾ 22
60 ⫾ 17
29 ⫾ 12
66 ⫾ 21† (16–37.5)
14 ⫾ 15† (2.8–26.2)
28 ⫾ 18† (4.7–37.5)
38 ⫾ 14† (3–19.4)
26 ⫾ 10
23 ⫾ 14
14 ⫾ 9† (3.4–20)
15.8 ⫾ 10.25* (5.1–10)
58.4 ⫾ 25
36.1 ⫾ 22.6* (15–29.4)
*p ⬍ 0.01 versus baseline; numbers between parentheses refer to the 95% confidence
intervals for difference of means.
although it was still more than that of the control group
(Fig. 3).
Relation of changes in LA size and function to LV
hemodynamics and clinical status. There were significant
relations between changes in LA volumes and LA function.
As LA volume before its contraction (LA pre-A volume)
decreased, LA ejection force decreased (r ⫽ 0.72, p ⬍
0.001, Fig. 4). Changes in LA ejection force were positively
related to the reduction in LA stroke volume (r ⫽ 0.66, p ⬍
0.01). Likewise, changes in LA KE were positively related
to changes in LA stroke volume (r ⫽ 0.77, p ⬍ 0.001, Fig.
5) and LA ejection force (r ⫽ 0.81, p ⬍ 0.001, Fig. 6).
There was a weak, albeit significant, relation between LA
maximal volume reduction and MR volume reduction (r ⫽
0.4, p ⬍ 0.05). A stronger relation was present, however,
with changes in LV pre-A pressure (r ⫽ 0.8, p ⬍ 0.01, Fig.
7). Regarding changes in LV passive filling volume, these
Changes in LV passive filling volume and LA size six
months after NSRT. The volumes in HOCM patients
were significantly larger than age-matched controls. Six
months after NSRT, LA volumes (max., min., pre-A and
stroke volume) were significantly reduced in comparison
with baseline values, although still larger than LA volumes
of the control group (Fig. 1). However, LV passive filling
volume increased after NSRT (Table 1; p ⬍ 0.05).
Changes in LA function six months after NSRT. Mean
LA ejection force in the control group was 8.4 ⫾ 3.4 kdyne.
Mean LA ejection force in HCM patients was significantly
larger. Six months after NSRT, mean LA ejection force was
lower although still more than that of the control group
(Fig. 2). Mean LA KE of the control group was 13.6 ⫾ 4
kerg. Mean LA KE in HOCM patients before NSRT was
significantly larger and decreased six months after NSRT
Figure 2. Left atrial (LA) ejection force in the control group, and
in the HOCM group pre- and post-NSRT (comparing controls
with HOCM patients pre-NSRT: p ⬍ 0.001, 95% confidence
intervals: 6.46 –23.5; comparing controls with HOCM patients
post-NSRT: p ⫽ 0.019, 95% confidence intervals: 1.3–13.6).
1126
Nagueh et al.
LV Filling and LA Size and Function After NSRT
Figure 3. Left atrial (LA) kinetic energy (KE) in the control
group, and in the HOCM group pre- and post-NSRT (comparing
controls with HOCM patients pre-NSRT: p ⬍ 0.001, 95%
confidence intervals: 30 –59.6; comparing controls with HOCM
patients post-NSRT: p ⫽ 0.001, 95% confidence intervals: 9.3–
36).
were positively related to reduction in LVOT gradient (r ⫽
0.5, p ⫽ 0.05), and to prolongation of exercise duration at
six months (r ⫽ 0.85, p ⬍ 0.01, Fig. 8).
DISCUSSION
In comparison with age-matched controls, HOCM patients
as shown in this study have increased LA volumes as well as
increased LA ejection force and kinetic energy. After
NSRT, LA volumes, ejection force and KE are reduced
concomitant with an increase in LV filling during early
diastole, and a statistically significant prolongation in exercise duration.
Figure 4. Regression plot of ⌬ LA pre-A volume versus ⌬ LA
ejection force (pre- and post-NSRT).
JACC Vol. 34, No. 4, 1999
October 1999:1123–8
Figure 5. Regression plot of ⌬ LA KE versus ⌬ LA SV (pre- and
post-NSRT).
Changes in LV passive filling volume six months after
NSRT. HOCM patients have enlarged LA due to impaired LV relaxation, and mitral regurgitation (14). Impaired LV relaxation leads to higher early diastolic LV
pressures, and thus lower transmitral pressure gradients.
Accordingly, HOCM patients usually have reduced LV
passive filling volume as demonstrated by radionuclide and
Doppler echocardiographic techniques (15–17). Nonsurgical septal reduction therapy improves LV relaxation (5), at
least in part through relief of LVOT obstruction and
increase in loads that aid relaxation and filling. It also
appears to improve LV compliance (5) through a reduction
in mass/volume ratio (4) as well as improvement in LV
relaxation. Accordingly, LV diastolic pressures are lower,
leading to an increase in LV passive filling volume.
Although reducing MR volume would be expected to
lower early diastolic LV filling through a reduction in LA ‘v’
wave pressure, this was not observed in our patient popu-
Figure 6. Regression plot of ⌬ LA KE versus ⌬ LA ejection force
(pre- and post-NSRT).
JACC Vol. 34, No. 4, 1999
October 1999:1123–8
Figure 7. Regression plot of ⌬ LA maximal volume versus ⌬ LV
pre-A pressure (pre- and post-NSRT).
lation. Most of this HOCM cohort had only mild MR,
which minimized the influence of this lesion on LV filling.
These changes in LV filling are particularly important
because HOCM patients usually have reduced LV filling
with exercise that results in a lower end-diastolic volume,
stroke volume (18), and, accordingly, reduced exercise
tolerance. Similar to observations with verapamil (16), we
observed an improvement in exercise duration that was
closely associated with the increase in LV passive filling
(Fig. 8).
LA size and function in HOCM patients and the effects
of NSRT. Left atrial contribution to LV filling is increased
in HOCM patients secondary to impaired LV relaxation.
As shown in the present study, LA volumes are much larger
in HOCM patients compared with control subjects. After
NSRT, LV diastolic pressures and MR volume are lower,
leading to significantly reduced LA volumes.
Nagueh et al.
LV Filling and LA Size and Function After NSRT
1127
Likewise, LA ejection force in HOCM patients is much
larger than in normal subjects secondary to increased pre-A
volume. The atria follow the Frank-Starling mechanism
(19 –21), leading to augmented contractility with increases
in LA preload. As noted previously, after NSRT the LV
passive filling volume increases and LA pre-A volume
decreases. Therefore, LA preload is reduced and accordingly
ejection force and stroke volume. Likewise, LA KE is
higher in HOCM patients because ejection force and stroke
volume are increased in comparison with normal individuals. After NSRT, LA ejection force and stroke volume are
reduced and therefore LA work.
It is interesting to note that this cohort of 30 HOCM
patients included a 32-year-old woman with frequent episodes of severely symptomatic atrial fibrillation. After
NSRT, her LA maximal volume was down from 132 ml to
45 ml, with no further episodes of atrial fibrillation as
assessed by history and Holter monitoring. Further observations will be needed to determine whether these changes
will affect the incidence of atrial fibrillation.
Study limitations. It would have been ideal had LA
pressure and stroke work been assessed invasively (11,22).
This would have necessitated transeptal LA catheterization,
with its possible risks in these very sick patients. Furthermore, the noninvasive assessment of LA kinetic energy has
been well validated against invasive standards with an
excellent correlation (r ⫽ 0.95) (11). Although the noninvasive methods used to derive LV filling pressures and
parameters of LA function may each have imperfections and
sources of error, the changes observed after NSRT (with
patients as their own control) were all in the same direction.
Acknowledgment
The authors thank Ms. Maria Frias for her expert secretarial
assistance.
Reprint requests and correspondence: Sherif F. Nagueh, Cardiology Section, Baylor College of Medicine, 6550 Fannin,
SM1246, Houston, Texas 77030. E-mail: [email protected].
REFERENCES
Figure 8. Relation of changes in exercise duration to those in left
ventricular passive filling volume.
1. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995;346:211– 4.
2. Knight C, Kurbaan AS, Seggewiss H, et al. Non-surgical septal
reduction for hypertrophic obstructive cardiomyopathy: outcome in
the first series of patients. Circulation 1997;95:2075– 81.
3. Seggewiss H, Gleichmann U, Faber L, Fassbender D, Schmidt H,
Strick S. Percutaneous transluminal septal myocardial ablation in
hypertrophic obstructive cardiomyopathy: acute results and 3-month
follow-up in 25 patients. J Am Coll Cardiol 1998;31:252– 8.
4. Lakkis NM, Nagueh SF, Kleiman NS, et al. Echocardiography guided
ethanol septal reduction for hypertrophic obstructive cardiomyopathy.
Circulation 1998;98:1750 –5.
5. Nagueh SF, Lakkis NM, Middleton KJ, et al. Changes in left
ventricular diastolic function six months after nonsurgical septal
reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999;99:344 –7.
6. Sasson Z, Yock PG, Hatle LK, Alderman EL, Popp RL. Doppler
1128
7.
8.
9.
10.
11.
12.
13.
14.
15.
Nagueh et al.
LV Filling and LA Size and Function After NSRT
echocardiographic determination of the pressure gradient in hypertrophic cardiomyopathy. J Am Coll Cardiol 1988;11:752– 6.
Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones
MA: DTI: a noninvasive technique for evaluation of left ventricular
relaxation and estimation of filling pressures. J Am Coll Cardiol
1997;30:1527–33.
Kircher B, Abbott JA, Pau S, et al. Left atrial volume determination by
biplane two-dimensional echocardiography: validation by cinecomputed tomography. Am Heart J 1991;121:864 –71.
Rokey R, Sterling LL, Zoghbi WA, et al. Determination of regurgitant fraction in isolated mitral or aortic regurgitation by pulsed
Doppler two-dimensional echocardiography. J Am Coll Cardiol 1986;
7:1273– 8.
Manning WJ, Silverman DI, Katz SE, Douglas PS. Atrial ejection
force: a noninvasive assessment of atrial systolic function. J Am Coll
Cardiol 1993;22:221–5.
Stefanadis C, Dernellis J, Lambrou S, Toutouzas P. Left atrial energy
in normal subjects, in patients with symptomatic mitral stenosis, and in
patients with advanced heart failure. Am J Cardiol 1998;82:1220 –3.
Appleton CP, Galloway JM, Gonzalez MS, Graballa M, Basnight
MA. Estimation of left ventricular filling pressures using twodimensional and Doppler echocardiography in adult patients with
cardiac disease. J Am Coll Cardiol 1993;22:1972– 82.
Nagueh SF, Lakkis NM, Middleton KJ, et al. Doppler estimation of
left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254 – 61.
Wigle ED, Sasson Z, Henderson MA, et al. Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy. A
review. Prog Cardiovasc Dis 1985;28:1– 83.
Bonow RO, Ostrow HG, Rosing DR, et al. Effects of verapamil on
JACC Vol. 34, No. 4, 1999
October 1999:1123–8
16.
17.
18.
19.
20.
21.
22.
left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy: pressure-volume analysis with a nonimaging
scintillation probe. Circulation 1983;68:1062–73.
Bonow RO, Dilsizian V, Rosing DR, Maron BJ, Bacharach SL, Green
MV. Verapamil-induced improvement in left ventricular diastolic
filling and increased exercise tolerance in patients with hypertrophic
cardiomyopathy: short- and long-term effects. Circulation 1985;72:
853– 64.
Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J.
Noninvasive assessment of left ventricular diastolic function by pulsed
Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:733– 42.
Lele SS, Thomson HL, Seo H, Belenkie I, McKenna WJ, Frenneaux
MP. Exercise capacity in hypertrophic cardiomyopathy: role of stroke
volume limitation, heart rate, and diastolic filling characteristics.
Circulation 1995;92:2886 –94.
Braunwald E, Frahm CJ. Studies on Starling’s law of the heart: IV.
observations on the hemodynamic functions of the left atrium in man.
Circulation 1961;24:633– 42.
Matsuda Y, Toma Y, Ogawa H, et al. Importance of left atrial
function in patients with myocardial infarction. Circulation 1983;67:
566 –71.
Sigwart U, Grbic M, Goy JJ, Kappenberger L. Left atrial function in
acute transient left ventricular ischemia produced during percutaneous
transluminal coronary angioplasty of the left anterior descending
coronary artery. Am J Cardiol 1990;65:282– 6.
Hoit BD, Shao Y, Gabel M, Walsh RA. In vivo assessment of left
atrial contractile performance in normal and pathological conditions
using a time-varying elastance model. Circulation 1994;89:1829 –38.