DOI: 10.1111/j.1540-8175.2011.01488.xC© 2011, Wiley Periodicals, Inc.

Left Atrial Systolic Force in Asymptomatic AorticStenosis

Giovanni Cioffi, M.D.,∗ Dana Cramariuc, M.D.,†‡ Morten Dalsgaard,§ Einar Skulstad Davidsen, M.D.,†‡Kenneth Egstrup, M.D.,¶ Giovanni de Simone, M.D.,∗∗ and Eva Gerdts, M.D.†‡∗Department of Cardiology, Villa Bianca Hospital, Trento, Italy; †Institute of Medicine, University of Bergen,Bergen, Norway; ‡Department of Heart Disease, Haukeland University, Bergen, Norway; §Department ofCardiology, Copenhagen University Hospital Rigshospitalitet, Copenhagen, Denmark; ¶Department ofMedicine, Svendborg Hospital, Svendborg, Denmark; and ∗∗Department of Clinical and ExperimentalMedicine, Federico II, University Hospital, School of Medicine, Naples, Italy

Background: There is a limited knowledge about left atrial (LA) systolic force (LASF) and its key deter-minants in patients with asymptomatic mild–moderate aortic stenosis (AS). Methods: We used baselineclinic and echocardiographic data from 1,566 patients recruited in the simvastatin ezetimibe in aorticstenosis study evaluating the effect of placebo-controlled combined simvastatin and ezetimibe treat-ment in asymptomatic AS. The LASF was calculated by Manning’s method. Low and high LASF weredefined as <5th and >95th percentile of the distribution within the study population, respectively.Results: Mean LASF in the total study population was 21 ± 14 kdynes/cm2. The determinants of LASFwere higher age, heart rate, body mass index, systolic blood pressure, left ventricular (LV) mass, mi-tral peak early velocity, maximal LA volume, and longer mitral deceleration time (multiple R2 = 0.37,P < 0.01). High LASF (78 patients) was characterized by abnormal LV relaxation in 90% of the cases.Low LASF (82 patients) was associated with restrictive LV filling pattern, absence of abnormal relaxationpattern, smaller maximal LA volume, and lower body mass index. In 40% of the patients with low LASF,estimated LV filling pressures were normal and the reduced LA force was explainable by an intrinsicsystolic LA dysfunction. Conclusions: In patients with asymptomatic AS, LASF was closely related tofilling pressure. Higher LASF invariably signifies the maximal LA effort to keep near normal LV fillingpressure; lower LASF belongs to a heterogeneous group of patients in which it is much more difficultto depict who have low LA preload or who have intrinsic systolic LA dysfunction. (Echocardiography2011;28:968-977)

Key words: LA systolic force, LA volume, LV diastolic function

In patients with aortic stenosis (AS), left atrial(LA) systolic force (LASF) increases to counter-balance the impairment in left ventricle (LV)filling and the progression of LV diastolic dys-function.1–4 Strong LA contraction contributesto recruit Frank–Starling forces, and to maintainLV performance and filling pressures. In previ-ous studies in hypertension it has been demon-strated that higher LASF is associated with a

Disclosure: The SEAS echocardiography core laboratory wassupported by the MSP Singapore Company, LLC, Singapore,a partnership between Merck & Co., Inc., and the Schering-Plough Corporation. Drs. Egstrup and Gerdts were membersof the SEAS Steering Committees and have received grantsupport from Merck & Co., Inc., the sponsor of the SEASstudy.

Address for correspondence and reprint requests: GiovanniCioffi, M.D., Division of Cardiology, Villa Bianca Hospital, viaPiave 78, Trento 38100, Italy. Fax: +39(461)916874; E-mail:gcioffi@villabiancatrento.i

high risk cardiovascular phenotype, character-ized by increased LV mass, concentric LV hy-pertrophy, and diastolic dysfunction.5–7 Further-more in the Strong Heart Study, which enrolledmiddle-aged and elderly North American Indianswith a high prevalence of hypertension, obesity,and diabetes, but without prevalent cardiovascu-lar disease, higher LASF was also associated withan increased rate of cardiovascular events inde-pendent of clinical risk factors and abnormal LVgeometry.8

Few studies have assessed LASF in AS. Fromthe simvastatin ezetimibe in aortic stenosis (SEAS)study, it has previously been published that LAvolume parallels AS severity.9 Although we havepreviously demonstrated that LASF is high in pa-tients with severe AS and concentric LV geom-etry,1 the relation of LASF to hemodynamic andclinical variables has not so far been systematicallyassessed in patients with asymptomatic mild–moderate AS. Accordingly, the present study

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was designed to assess correlates of LASF inpatients with asymptomatic AS, and to charac-terize groups of patients with particular low orhigh LASF.

Methods:Study Population:The SEAS study population included 1,873 pa-tients (aged 45–85 years) with asymptomaticAS to a 4.3 year, double-blind, and placebo-controlled treatment with combined simvastatinand ezetimibe to evaluate the effect on AS pro-gression and cardiovascular morbidity and mor-tality. Study protocol and main outcomes havebeen published.10 The AS was defined as aor-tic valve thickening accompanied by a Doppler-measured aortic peak flow velocity ≥2.5 m/secand ≤4.0 m/sec. The presence of other signifi-cant valvular disease, atrial fibrillation, establishedcoronary, cerebral and/or peripheral vascular dis-ease, type 2 diabetes, renal insufficiency (definedas serum creatinine >180 μmol/L), LDL choles-terol >6 mmol/L, or ongoing or any guideline in-dication for lipid-lowering therapy, were consid-ered as exclusion criteria. All patients gave writteninformed consent. The SEAS trial was approvedby ethical committees in all participating coun-tries.10 Concomitant hypertension was defined ashistory of hypertension reported by the attend-ing physician. Obesity was diagnosed accordingto the clinical guidelines of National Institute ofHealth.11 This study of population include the1,566 patients in whom baseline LASF could becalculated.

Echocardiography:Transthoracic echocardiography was performedaccording to a standardized protocol at 173European study sites, as previously reported.12

Images were stored on VHS video tapes, CDs,or MO disks, and forwarded for interpretationand measurements at the SEAS Echocardiogra-phy Core Laboratory at Haukeland UniversityHospital, Bergen, Norway. The LV quantificationwas performed following to the American So-ciety of Echocardiography guidelines.13 The LVmass was normalized for height to the powerof 2.7 and LV hypertrophy was defined as LVmass ≥49.2 g/m2.7 for men and ≥46.7 g/m2.7 forwomen.14

The LV volumes and stroke volume were mea-sured by the biplane method of disks,13 and usedto generate ejection fraction. Stroke volume wasnormalized for height at the allometric powerof 2.04 (SVI) to account for its nonlinear varia-tion with body size.15 Myocardial contractility wasassessed by midwall shortening and by end-systolic stress-corrected midwall shortening.16

Maximal LA volume was computed from two-dimensional apical four-chamber view using thearea–length method and normalized for bodyheight in the third power.17,18

Pulsed-wave transmitral Doppler signal wasobtained with the sample volume placed betweenthe mitral cusp tips and in the LV outflow tract inapical four- and five-chamber views to measureisovolumic relaxation time (IVRT), peak early (E)and late (A) transmitral flow velocity (cm/sec), E/Aratio, deceleration time of E velocity (DTE) (msec),time–velocity integral of E- and A-waves (cm),and LA filling fraction (%, calculated by dividingthe component time–velocity integral by the totaltime–velocity integral). E/A ratio <1 and >1.5 andDTE < 150 msec or >250 msec were consideredabnormal.19 The IVRT < 60 or >100 was con-sidered abnormal.19,20 Patients were classified ac-cording to the following four diastolic patterns19:“abnormal relaxation” (identified when IVRT was>100 msec and DTE > 250 msec and E/A ratio< 1.0), “restrictive” (IVRT < 100 msec, DTE <150 msec and E/A ratio > 1.5), “normal” (IVRT <100 msec, DTE > 150 msec, <250 msec and E/Aratio between 1.0 and 1.5), and “pseudonormal”(IVRT > 100 msec, DTE > 150 msec, <250 msecand E/A ratio between 1.0 and 1.5). A maximal LAvolume index >26 mL/m2 was also used to distin-guish between patients with normal LA pressureand pseudonormal or restrictive LV filling.21 Pa-tients with E + A fusion (peak summation) wereexcluded from the analysis.

Mitral LASF was calculated using a validatedequation22:

LASF = 0.5 × 1.06 × MOA × (peak A velocity)2,

where 1.06 is the blood density, MOA is the mi-tral orifice area calculated from the mitral annulusdiameter measured from the apical four-chamberview and A is atrial wave of transmitral flow mea-sured as reported above.

Aortic valve area was calculated by the conti-nuity equation method and normalized for bodysurface area.

Statistical Analysis:Data are reported as mean values ±1 standarddeviation. Between-group comparisons of cate-gorical and continuous variables were performedby chi-square test and analysis of variance. Covari-ates of LASF were assessed using least squared lin-ear regression. Multiple linear regression analysiswas used to evaluate independent relations ofLASF with variables significantly associated inunivariate analysis. In-model tolerance wascalculated to evaluate multicollinearity. Pretestminimal accepted tolerance was ≥0.80. Sub-groups of patients with low LASF and high LASF

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were identified from LASF <5th and >95th per-centile of the distribution of the LASF in the studypopulation, respectively. Multivariate logistic re-gression analyses were used to assess covariates oflow and high LASF. The following variables wereintroduced in the models: age, body mass index,heart rate, systolic blood pressure, LV mass index,cardiac output, LA volume, transaortic peak gradi-ent, mitral peak E-wave, DTE, IVRT, and trasmitralflow pattern. In this analysis we did not considerthe transmitral peak A-wave velocity (by defini-tion, the main determinant of LASF). A 2-tailedvalue of P ≤ 0.05 was used to reject the nullhypothesis.

Results:Correlates of LASF in the Total StudyPopulation:Clinic and echocardiographic characteristics ofthe total study population and the subgroups ofpatients with low or high LASF are presented inTable I. Mean LASF in the study population was21 ± 14 kdynes/cm2. Univariate covariates ofLASF are presented in Table II. In multivariate lin-ear regression including all significant univariate

variables, older age, higher values of heart rate,body mass index, systolic blood pressure, LA vol-ume, LV mass, mitral peak E velocity, and DTEwere independently associated with higher LASF(Table III).

High LASF:The 95th percentile of LASF in the total studypopulation was 50.0 kdynes/cm2. Patients ex-ceeding this value were 78 (mean LASF 64.1 ±16.3 kdynes/cm2). In comparison with thosewithout high LASF, they had higher heart rate,body weight, blood pressure, LV mass, and LAsize. Prevalence of patients receiving any anti-hypertensive treatment, diuretics, ACE inhibitors,AT1-receptors blockers and beta-blockers, andthe number of antihypertensive drugs were simi-lar between these two groups. More patients withhigh LASF received calcium antagonists (28% vs16%, P = 0.01) than patients without high LASF.Considering the parameters of diastolic LV func-tion, patients with high LASF were characterizedby higher mitral peak E- and A-wave, lower E/A ra-tio, and prolonged DTE (Table I). Figure 1 showsthe prevalence of the four LV diastolic filling

TABLE I

Main Clinical and Echocardiographic Characteristics of 1,566 Study Patients

Total Study Population Low LASF High LASFVariables 1,566 Patients 82 Patients 78 Patients

LASF (kdynes/cm2) 21 ± 14 4.6 ± 1.2∗

64.1 ± 16.3∗

ClinicalAge (years) 67 ± 10 62 ± 10

∗69 ± 9

Male gender (%) 61 74∗

50Body mass index (kg/m2) 27 ± 4 25 ± 4

∗29 ± 6

Obesity (%) 20 11∗

37∗

Systolic blood pressure (mmHg) 146 ± 20 136 ± 18∗

151 ± 20∗

Diastolic blood pressure (mmHg) 82 ± 10 79 ± 9 82 ± 10Heart rate (beats/minute) 65 ± 11 63 ± 13 72 ± 12

∗

History of hypertension (%) 50 46 53Antihypertensive treatment (%) 43 41 46

EchocardiographicTransvalvular peak gradient (mmHg) 39 ± 14 40 ± 14 43 ± 14

∗

Aortic valve area (cm/m2) 0.67 ± 0.23 0.68 ± 0.19 0.65 ± 0.24LV end-diastolic diameter (cm/height) 2.99 ± 0.32 2.97 ± 0.30 3.06 ± 0.40LV mass index (g/m2.7) 44 ± 14 45 ± 15 51 ± 19

∗

LV ejection fraction (%) 75 ± 4 74 ± 18 76 ± 23Stress-corrected mid-wall shortening (%) 94 ± 18 92 ± 16 94 ± 20Left atrial diameter (cm/height) 2.2 ± 0.4 2.1 ± 0.4

∗2.4 ± 0.4

∗

Left atrial maximum volume (mL/m2) 32 ± 10 30 ± 11∗

41 ± 13∗

Mitral peak E velocity (cm/sec) 73 ± 20 61 ± 20∗

106 ± 31∗

Mitral peak A velocity (cm/sec) 83 ± 20 42 ± 8∗

138 ± 21∗

Mitral E/A ratio (cm/sec) 0.93 ± 0.32 1.53 ± 0.8∗

0.77 ± 0.2∗

Mitral E deceleration time (msec) 230 ± 77 211 ± 69∗

274 ± 120∗

Isovolumic relaxation time (msec) 102 ± 23 99 ± 22 98 ± 22

LV = left ventricular.∗P < 0.05 versus total study population.

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TABLE II

Variables Significantly Related to Left Atrial Systolic Force (Expressed as Continuous Variable): Univariate Regression Model

Variables Pearson’s Correlation Coefficient P

DemographicsAge (years) 0.17 <0.001Female gender (%) 0.11 <0.001Body height (m) 0.10 <0.001Body weight (kg) 0.12 <0.001Body mass index (kg/m2) 0.20 <0.001Heart rate (beats/minute) 0.22 <0.001Systolic blood pressure (mmHg) 0.06 0.030Diastolic blood pressure (mmHg) 0.16 <0.001

Left ventricular geometryLV mass index (g/m2.7) 0.13 <0.001

Left ventriclular performance and systolic functionCardiac output (l/minute) 0.15 <0.001

Left ventricular diastolic function and left atrial sizeMitral peak E velocity (cm/sec) 0.44 <0.001Mitral peak A velocity (cm/sec) 0.87 <0.001Mitral E/A ratio (cm/sec) −0.37 <0.001Mitral E deceleration time (msec) 0.21 <0.001Time-velocity integral of mitral E-wave (cm) 0.38 <0.001Time-velocity integral of mitral A-wave (cm) 0.68 <0.001Isovolumic relaxation time (msec) 0.02 nsLeft atrial filling fraction (%) 0.32 <0.001Left atrial diameter (cm/height) 0.21 <0.001Left atrial maximum volume (mL/m2) 0.30 <0.001

Aortic valve severityTransaortic peak gradient (mmHg) 0.08 0.002

LV = left ventricular.

patterns identified in the study subgroups. In pa-tients with high LASF abnormal relaxation pat-tern was identified in 90% of the subjects. Only2% of these patients presented a LV filling pat-tern (pseudonormal or restrictive) suggestive forelevated LV filling pressures (Fig. 2). Multiple lo-gistic regression analyses showed that high LASF

was associated with the presence of an abnormalrelaxation pattern, greater maximal LA volume,and higher heart rate (Table IV, Model A).

Low LASF:The 5th percentile of LASF in the total studypopulation was 6.0 kdynes/cm2. Patients with

TABLE III

Variables Independently Related to Left Atrial Systolic Force (Expressed as Continuous Variable): Multivariate Model (MultipleLinear Regression Analysis)

Variables Standardized Coefficients Beta P

Total study populationMitral peak E velocity (cm/sec) 0.41 <0.001Mitral E deceleration time (msec) 0.23 <0.001Heart rate (beats/minute) 0.20 <0.001Left atrial maximum volume (mL/m2) 0.17 <0.001Age (years) 0.13 <0.001Body mass index (kg) 0.08 <0.001LV mass index (g/m2.7) 0.07 0.004Systolic blood pressure (mmHg) 0.05 0.030

Final results multivariate regression modelIntercept = 59.9 SEE 11.0, R2 = 0.37 0.61 <0.001

Variables which were considered in the analysis but did not enter in the model: Female gender, diastolic blood pressure, cardiacoutput, and trans-aortic peak gradient.

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Figure 1. Prevalence of LV diastolic filling patterns in patients with asymptomatic aortic stenosis divided into groups with lowleft atrial systolic force (LASF, <6 kdynes/cm2), average (between 6.0 and 50.0 kdynes/cm2) or high LASF (>50 kdynes/cm2).

LASF lower than this value were 82 (mean LASF4.6 ± 1.2 kdynes/cm2). They were younger,more frequently male, had lower heart rate, bodyweight, blood pressure, and LA size, and were

characterized by higher E/A ratio and shorter DTEthan patients without low LASF (Table I). Fig-ure 3 summarizes these results showing the preva-lence of abnormal E/A ratio, DTE and IVRT in

Figure 2. Relationship between left atrial systolic force (LASF) and mitral peak E/A velocity ratio in the patients with high (n =78) and low (n = 82) LASF. Scatter plot of exponential correlation is shown. Approximately 50% of patients with low LASF liein the intrinsic systolic LA dysfunction area (defined as abnormally low LASF associated with normal transmitral flow pattern orabnormal relaxation pattern), which includes also the very small group of patients with low LASF and pseudonormal pattern whodo not belong to this phenotype.

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TABLE IV

Variables Independently Related to Low and High Left Atrial Systolic Force, and Intrinsic Left Atrial Pump Failure (Expressed asCategorized Variable): Comparison between Each Group and the Total Population (Multiple Logistic Regression Analysis)

Variables Exp Beta C. I. r P

Model A: Determinants of high LASFAbnormal relaxation versus no abnormal relaxation 4.00 1.86–8.66 0.13 0.004Left atrial maximum volume (mL/m2) 1.21 1.15–1.26 0.33 <0.001Heart rate (beats/min) 1.05 1.03–1.07 0.19 <0.001

Model B: Determinants of low LASFRestrictive versus nonrestrictive pattern 10.07 5.45–18.61 0.29 <0.001No abnormal relaxation vs abnormal relaxation 5.01 2.70–8.90 0.20 <0.001Body mass index (kg/m2) 0.92 0.85–0.99 −0.07 0.020Maximal left atrial volume (mL/m2) 0.91 0.85–0.97 –0.10 0.050

Model C: Determinants of intrinsic systolic LA dysfunctionLeft atrial maximum volume (mL/2) 0.83 0.74–0.93 0.16 0.002Age (years) 0.95 0.92–0.99 −0.11 0.010

Variables introduced in the models: age, body mass index, heart rate, systolic blood pressure, left ventricular mass index, cardiacoutput, left atrial volume, mitral peak E-wave, deceleration time of E-wave, isovolumic relaxation time, and Doppler diastolicpatterns.

patients with low and high LASF. Restrictive pat-tern (tested vs. the nonrestrictive one) and theabsence of abnormal relaxation pattern (tested vsthe abnormal one) together with smaller LA vol-ume and body mass index were the independentdeterminants of low LASF (Table IV, Model B).

Among these 82 patients with low LASF, twodifferent phenotypes were found. In 49 patients(60%), restrictive or pseudonormal LV diastolicpattern was present, suggesting high LV fillingpressure. The remaining 33 (40%), had abnormalrelaxation or normal LV diastolic pattern, possi-bly indicating normal LV filling pressure (Fig. 1).Thus, in these patients, low LASF could not be ex-

plained by increased LA afterload, and most likelywas caused by an intrinsic impairment in LA con-tractility or low LA preload (Fig. 2).

Low LASF–Normal LV Filling Pressure:Compared to the total study population, these 33patients were younger, had lower systolic bloodpressure, smaller left atrium, more often normalLV diastolic filling pattern (49% vs. 20% in wholepopulation), and included more men, whereasno difference was found in LV geometry, LV sys-tolic function, or AS severity. In comparison to therest of study population without this phenotype,low LASF normal LV filling patients had similar

Figure 3. Prevalence of abnormal mitral E/A velocity ratio (defined as <1 or >1.5), abnormal deceleration time of mitral Evelocity (DTE), defined as <150 msec or >250 msec, and abnormal isovolumic relaxation time (IVRT), defined as <60 msec or>100 msec, in patients with low and high left atrial systolic force (LASF).

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Figure 4. The relation between left atrial (LA) systolic force (LASF) and maximal LA volume in patients with normal transmitralflow pattern or abnormal relaxation pattern. Scatter plot of linear correlation is shown. Patients with low LASF have the smallestvalues of maximal LA volume in comparison with patients without low LASF.

LV stroke volume, cardiac output, and prevalenceof low stroke volume (53% vs 42%, P = ns; re-spectively), suggesting the existence of a similarpreload condition between the groups. In mul-tiple logistic regression analysis, smaller maximalLA volume and younger age were independentdeterminants of this phenotype (Table IV; ModelC). Figure 4 shows the relationship between LASFand maximal LA volume in patients with ab-normal LV relaxation or normal transmitral flowpattern.

Discussion:This is the first large study to report LASF and itscovariates in patients with asymptomatic mild–moderate AS. The present investigation showsthat in these patients LASF is related to olderage, higher values of heart rate, body mass index,systolic blood pressure, LV mass, and Doppler-derived indexes of LV diastolic function suggest-ing a close dependence on LV filling pressure.Furthermore, our study gives a picture of highand low LASF conditions; the former mostly indi-cates the maximal LA effort to keep the LA pres-sure normal, so that the finding of an impaireddiastolic relaxation pattern is a consequence offorceful empting of the left atrium, the latter be-longs to a heterogeneous group of patients whichis much more difficult to depict.

Determinants of LASF:Among the two variables used for calculatingatrial force by Manning’s method, mitral peak Avelocity was stronger associated with LASF thanmitral valve area (r coefficient 0.87 vs 0.30, re-spectively). This finding indirectly confirms thedynamics of LASF and its dependence on LVpreload, and is in line with previous publica-tions.7,23,24 Whereas mitral valve area is mainlyassociated with LA volume, reflecting mean LVfilling pressure over time,25 mitral peak A ve-locity is mostly associated with actual LV fillingpressure.25–27

In this study, a longer DTE was associated withhigher LASF in the multivariable model, suggest-ing a compensatory increase in LA myocardialcontractility in response to an impaired LV relax-ation. This hemodynamic relation has been clearlydescribed in patients with severe AS by Vanover-schelde et al.28 They demonstrated, using an inva-sive approach, that the subgroup of patients withnormal LV filling pressures and ejection fractionhad a delayed diastolic filling, occurring preva-lently during the late phase of diastole, which isthe typical phenotype of impaired LV relaxation.Our findings add to their report by demonstrat-ing that higher LASF also is associated with highermitral peak E velocity. However, peak A velocityand A time–velocity integral were relatively larger,with the net result of a shift of LV filling from early

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to late diastole and lower E/A ratio in this pa-tient group, in accordance with Vanoverschelde’sfindings. More than two thirds of our patientsshowed an abnormal LV relaxation pattern thatwas widely associated with high levels of LASF.In contrast, no association was found betweenLASF and IVRT, the hallmark of impaired relax-ation, even when the two groups with high orlow LASF were analyzed separately. This findingdoes not consistently fit with the relations previ-ously described, making the interpretation of ourresults more challenging. A first possible explana-tion may be found in the relation between IVRTand LV filling pressures which is quite strong inpatients with LV systolic dysfunction, but is signif-icantly weakened in presence of normal LV ejec-tion fraction.29 This observation implies that inour patients who have normal LV ejection frac-tion the accuracy of the estimation of LV dias-tolic properties by IVRT is low. The lack of corre-lation between LASF and IVRT may also dependon the distribution of impaired intrinsic LV my-ocardial contractility, LV geometry, and myocar-dial stiffness in our study population.19,30 Thesevariables, which could be possibly influenced byolder age, presence of subclinical myocardial is-chemia, and/or arterial hypertension beyond aor-tic valve disease, may also explain why LASF waspredicted by LV mass and not by the AS severityin this population, as resulted in our recent expe-rience in which we analyzed 94 patients with var-ious degrees of AS.31 The relations between LASFand Doppler indexes of early LV diastolic filling,described above, were independent of age andheart rate; two physiological conditions whichhave a relevant impact on LASF, and which arewell-documented in several studies as well as inours.32–35 Of interest, no parameter of LV systolicperformance or function was related to LASF inour patients.

Low and High LASF Subgroups:Patients in the high LASF subgroup showed a ho-mogenous hemodynamic profile. LV filling pres-sure was estimated as normal in 98% of these pa-tients, and high LASF status invariably indicatesin these patients that the left atrium is provid-ing maximal compensation to maintain normalLV filling pressure. Elevated LASF represents a cru-cial adaptive mechanism to avoid critical changesin the hemodynamic status of subjects with ASas well as of other cardiac diseases such as idio-pathic hypertrophic cardiomyopathy and chronicheart failure.31 In all these conditions, high LASFis independently related to increased LA size, thathas been recently identified as independent pre-dictor of long-term mortality in patients with se-vere AS.35 In this view, our findings suggest thatin patients with mild–moderate AS, the increase

in LA size is paralleled by an increase in LA per-formance, which mirrors a greater need of com-pensation for hemodynamic overload due to theaortic valve disease. This condition may also ex-plain why occurrence of atrial fibrillation is oftenhighly symptomatic in these patients.

On the other side, subjects in the low LASFsubgroup had heterogenic LV diastolic filling pat-terns, reflecting differences in the degree of LVdiastolic dysfunction and hemodynamic status. In59% of these patients, a restrictive or pseudonor-mal pattern was found, reflecting the presence ofhigh LV filling pressures. In this condition of in-creased LA afterload, LASF may be largely under-estimated, so that reading this finding as a stateof impaired LA contractility is methodologically amistake.

In the remaining 41% of patients in the lowLASF subgroup, abnormal LV relaxation or normalLV diastolic pattern was found, suggesting normalLA afterload and low LASF to reflect lack of activa-tion of LA adaptation mechanisms caused by anintrinsic failure of pump function. Alternatively,low LASF in these patients could be due to vigor-ous LV relaxation and/or untwisting (physiologicmechanism typically detected in the athletes ofendurance with eccentric LV hypertrophy) whichcreates suction and favors LV passive filling affect-ing LA contraction. However, this is less likely inhearts with AS which tend to remodel in a con-centric fashion.

An intrinsic systolic LA dysfunction has beendescribed in various types of cardiomyopathiesand was associated with LA thrombus forma-tion.36,37 A severe LA infiltration of fibrosis or amy-loid has been supposed as etiologic mechanismof intrinsic mechanical LA systolic function in pa-tients with dilated or restrictive cardiomyopathy,respectively, however it may also be caused bysubclinical coronary artery disease, as suggestedfrom previous reports.26,36,37 In our patients, thelast condition might be a possible etiology. How-ever, patients with history or clinical symptoms ofcoronary artery disease where not included in theSEAS trial.

Low LASF associated with normal LV fillingpressure may be also due to low LA preload. How-ever, this hemodynamic status, which stronglyinfluences LASF,7 is characterized by low strokevolume and cardiac output, and this was not thecase of our patients in whom the values of theseparameters were similar to those with normal orhigh LASF.

Study Limitations:The SEAS study included 173 study centers inseven European countries and inclusion of pa-tients was done during the period 2002–2004. It

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was necessary in this setting to keep the echocar-diography protocol simple. Recording of pul-monary venous flow, tissue Doppler echocardio-graphy, and LA strain was not a part of theprotocol. Analysis of LA function by the variablesderiving from these techniques would have beenhelpful in clarifying pathophysiological aspects ofLA function in our patients.38 Furthermore, in-vasive hemodynamic work up was not includedin this study of asymptomatic mild to moder-ate AS patients. Thus, although one of the maincauses of increased LASF is related to LV dias-tolic dysfunction, we were unable to report in-vasive hemodynamic data, nor could we providereal hemodynamic correlates of our echocardio-graphic findings. However, we used a straight-forward and shared19–21,27,39 approach whichprovided a plausible account of the observed rela-tionships between LV and LA changes in patientswith AS. In particular, we chose to include in thelist of potential covariates of LASF, the transmitralDoppler flow patterns, which are the resultant ofthe interaction of many diastolic properties andvariables, and express the hemodynamic status ofthe patients. By this way, we could take into ac-count and analyze the possible interferences be-tween LV filling pressures and LASF.

Clinical Implications and Conclusions:The AS represent a pathophysiological model ofLV pressure overload well suited for studies of therelation between LASF and clinical features, andmyocardial LV afterload and indices of LV systolicand diastolic function. Considering the preloaddependence of Doppler-derived indexes of LV di-astolic function and LA systolic function, how-ever, the absence of elevated LV filling pressure isthe mandatory condition where LASF can be cor-rectly estimated. In patients with mild–moderateAS, high LASF is related (together with older ageand increased LV mass) to diastolic dysfunction,and may be a physiologic mechanism activated tokeep near normal the LV filling pressure; further-more, both high and low LASF may be indicative(as different faces) of a susceptibility for atrial fib-rillation. Thus, in patients with mild–moderate AS,LASF represents a simple parameter, which pro-vides useful additional information about the me-chanical LA function, hemodynamic status, andLV diastolic function.

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