Participants

Figure 1 is a diagram of our present and previous studies. Between December 2010 and August 2013, a total of 520 patients with chronic severe MR undergoing echocardiography in the outpatient clinic were screened. The initial exclusion criteria were (1) LVEF < 60%; (2) MR of Carpentier type I or III, caused by regional or global LV remodeling without structural abnormalities of the MV (functional or ischemic MR) and MR caused by rheumatic heart disease; (3) coexistent aortic valve disease and mitral stenosis of more than a mild degree; (4) prior open heart surgery; and (5) congenital heart disease.

The remaining 168 patients with chronic severe primary MR (caused by diseases involving the MV) and LVEFs ≥ 60% received surgical referrals guided by current recommendations and were excluded if any of the following was present: (1) symptoms of heart failure or effort-related limitations in daily activities (unable to climb two flights of stairs, to run a short distance, or to walk uphill) on the basis of a medical record, (2) prior admission for heart failure, (3) planned MV surgery at the time of index echocardiography, and (4) inadequate image acquisition. Finally, only asymptomatic patients (New York Heart Association functional class I) with MR designated as Carpentier type II (MV prolapse or flail, adjudicated by two cardiologists) entered our study, including (1) asymptomatic patients without surgical indications, (2) asymptomatic patients with class IIA surgical indications (LV end-systolic dimension > 40 mm, pulmonary hypertension, or AF rhythm) but refused surgery.

Severe MR was diagnosed using a multiparametric approach, including evaluation of the vena contracta width, the effective regurgitant orifice area, the regurgitant volume, and the presence of systolic pulmonary venous flow reversal aligned with American Society of Echocardiography criteria.

Every 1 to 3 months, patients were followed up at the clinic by their original cardiovascular specialists, and symptoms and signs of heart failure were carefully evaluated. For patients who developed symptoms, surgical referrals were made, and follow-up echocardiography was arranged, whether at the outpatient clinic or during hospitalization (different vendors might be used). The final surgical decision, however, was based on the patient’s preference after communication with independent surgeons blinded to the study. For asymptomatic patients, whether follow-up echocardiography was arranged was left to the discretion of the primary care physician. The composite end points of our study after index echocardiography were designated as cardiovascular mortality or MV surgery (repair or replacement) caused by new-onset heart failure (symptom exacerbation requiring hospitalization with radiographic evidence of pulmonary congestion or heart failure progression identified in the outpatient clinic). This rationale reflects what is commonly seen in Taiwan; most asymptomatic patients declined MV surgery until symptoms were patent, regardless of the presence of a class IIA surgical indication. Hence, MV surgery triggered by symptoms was denoted as an end point.

All patients were followed until they either reached the study end point or reached the end of study follow-up. There was no loss to follow-up as of August 2014. If a patient experienced any cardiac event eventually leading to cardiovascular death or a subsequent firm surgical decision, the time to the end point was signified as the time to that cardiac event. Functional class at enrollment, medical history, any adverse cardiac events, and the composite end point (including the cause) during follow-up were obtained from medical records and adjudicated by two cardiologists. Telephone interviews were conducted to assess the condition of patients between office visits. In the study, brain natriuretic peptide level was not routinely acquired. The study adhered to the Declaration of Helsinki and received approval from the Human Research and Ethics Committee of National Cheng Kung University Hospital (A-ER-102-322).

Echocardiography

Standard echocardiography was performed with Doppler studies (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway), with a 3.5-MHz multiphase-array probe in subjects lying in the left lateral decubitus position. Chamber dimension and wall thickness were measured using the 2D-guided M-mode method, and LVEF was measured using the 2D biplane method of disks, according to American Society of Echocardiography recommendations. LV mass was measured using the M-mode method and indexed to body surface area. Transmitral Doppler flow velocity was obtained from an apical four-chamber view, and peak early fllling velocity (E), peak atrial velocity (A), early fllling–to–atrial velocity ratio (E/A), and mitral deceleration time were measured. Pulse Doppler tissue imaging was performed from the medial and lateral annulus, and peak systolic annular velocity (S) and the average value of early diastolic annulus velocity (e′) were measured. The E/e′ ratio was used as an index of LA pressure. Two-dimensional images were acquired from apical four-chamber and two-chamber views for three cardiac cycles and digitally stored, at a frame rate of 50 to 90 frames/sec. The images were analyzed offline using computer software (EchoPAC PC 09; GE Vingmed Ultrasound AS).

Volumetric Measurements of the Left Atrium

LA volume was measured using the biplane area-length method from 2D echocardiography. LA area was measured with planimetry for four-chamber and two-chamber views by tracing the endocardial border, excluding the confluence of the pulmonary veins and the LA appendage. LA length was measured from the midline of the plane of the mitral annulus to the opposite aspect of the left atrium. LA volume was measured at end-systole and end-diastole and calculated as 0.85 × four-chamber area × two-chamber area/average of the two lengths. The maximal LA volume during LV end-systole (LAVs) and the minimal LA volume during LV end-diastole (LAVd) were obtained. LA total emptying fraction (LATEF) was calculated as [(LAVs − LAVd)/LAVs] × 100%. LA size was represented by LAVs and indexed to body surface area (LA volume index [LAVi]). Measurements were repeated three times in each subject, and the average was used for analysis.

Deformation Analysis of the Left Ventricle and Left Atrium by STE

LV GLS was measured from three apical views using automated function imaging software, as reported in detail previously, with very low intraobserver and interobserver variability.

The method for LA deformation analysis by STE was described in detail in our previous studies. The endocardial border of the left atrium was manually deflned using a point-and-click technique. Epicardial surface tracing was automatically generated by the system, creating a region of interest that was manually adjusted to cover the full thickness of the myocardium in the systolic frame. The width of the smallest region of interest was 8 mm. Before processing, a cine loop preview was used to conflrm whether the internal line of the region of interest followed the LA endocardial border throughout the cardiac cycle. Time-strain and time–strain rate plots were produced automatically by the software. Because of the inclusion of patients with AF, we analyzed only peak positive strain of the left atrium (LASp) and strain rate in the LA filling phase (LASRr) and the strain rate in the LA conduit phase (LASRc) in LV early fllling, while discarding the peak negative strain and strain rate after the P wave. We further divided the LA wall into eight segments: the basal septal, middle septal, basal lateral, and middle lateral segments in the four-chamber view and the basal inferior, middle inferior, basal anterior, and middle anterior segments in the two-chamber view. The averages of LASp, LASRr, and LASRc in these eight segments were used for analysis ( Figure 2 ).

The LA strain curve derived from STE. LASp can be obtained from both apical four-chamber and two-chamber views. The white arrow indicates LASp of the basal septal ( top ) and basal inferior ( bottom ) walls, respectively.

Reproducibility

Two independent investigators performed the analysis. Twenty patients were randomly selected for evaluation of the interobserver variability of LA strain and strain rate measurements by two independent observers. To determine intraobserver variability, the same measurements were repeated 1 week apart. Mean percentage error was calculated as the absolute difference divided by the average of the two observations.

Statistical Analysis

Statistical analysis was performed using SPSS version 18.0 (SPSS, Inc, Chicago, IL). All data are expressed as mean ± SD unless otherwise stated. All parameters reflecting LA phasic function (LASp, LASRr, and LASRc) were approximately normally distributed. By using the χ ² test for categorical variables and the independent-samples t test for continuous variables, we first identified factors with significant correlations to enter into multivariate logistic regression analysis ( P < .05). To determine whether atrial deformation parameters could predict the composite end point while avoiding collinearity between them (a linear relationship existed between LASp and LASRr; r = .672, P < .01), separate multivariate logistic regression models were used for each atrial parameter, to which we added factors obtained in the first step as well as other well-accepted factors affecting atrial deformation with documented importance regardless of their significance. Finally, multivariate Cox regression analysis was applied to identify independent predictors of the end points. P values < .05 were considered to indicate statistical signiflcance. The Kaplan-Meier method was used with a log-rank test to demonstrate differences between strata in terms of end points.

Differences between Patients Regarding Baseline Rhythm and Surgical Indication

Comparing subgroups with baseline sinus rhythm or AF, the latter was older; had lower LATEF, GLS, LASp, and LASRr; and had higher heart rates, LV mass index values, and LAVi values. Comparing patients with and those without baseline class IIA surgical indications, the former group exhibited higher heart rates, LV mass index values, E/e′ ratios, LAVi values, and PASPs, as well as reduced GLS, LATEF, LASp, and LASRr ( Supplemental Table 1 ).

Differences between Patients with and Those without End Points

Clinical characteristics did not differ significantly between patients with and those without end points ( Table 1 ). Among the echocardiographic parameters, LASp, LASRr, and LV end-systolic volume index (LVESVi) varied between groups in terms of end points, but not LVEF, indexed LV end-systolic dimension, LV GLS, E, E/e′ ratio, LAVi, effective regurgitant orifice area, regurgitant fraction, or PASP ( Table 2 ).

Between patients with ( n = 27) and those without ( n = 77) heart failure, LASp (22.5 ± 9.8% vs 27.6 ± 9.1%, P = .019) and LASRr (1.97 ± 0.6 vs 2.35 ± 0.6 1/sec, P = .006) varied significantly ( Supplemental Table 3 ).

Determinants of an Unfavorable Prognosis

Two multivariate Cox regression models were used, to which LVESVi and factors affecting atrial deformation were added (age, status of AF, and LAVi) in both models ( Table 3 ). After analysis, LASp and LASRr remained significant. By dividing patients into equal numbers according to the median values of LASp (26%) and LASRr (2.2 1/sec) in two multivariate Cox regression models, both LASp < 26% (odds ratio, 3.606; 95% CI, 1.294–10.052; P = .014) and LASRr < 2.2 1/sec (odds ratio, 2.857; 95% CI, 1.078–7.572; P = .035) predicted death or MV surgery ( Table 3 ). Between-stratum outcome differences were demonstrated by the Kaplan-Meier survival curves plotted accordingly (log-rank P < .05 for both) ( Figure 3 ). We also attempted to find any sensitive cutoff values derived from the age-matched healthy sample ( Supplemental Figures 1 and 2 ). For determinants of heart failure, LVESVi, LASp, and LASRr remained significant after multivariate analysis ( P < .05 for both) ( Supplemental Table 4 ).

Table 3

Multivariate Cox regression analysis for prediction of death and MV surgery

Death or MV surgery	Model 1: LASp		Model 2: LASRr
	HR (95% CI)	P	HR (95% CI)	P
Age	0.975 (0.935–1.015)	.220	0.991 (0.956–1.028)	.636
AF	0.861 (0.243–3.054)	.817	0.902 (0.253–3.216)	.873
LAVi	1.000 (0.974–1.026)	.987	0.993 (0.967–1.020)	.621
LVESVi	1.062 (0.996–1.132)	.068	1.069 (1.000–1.143)	.051
LASp	0.916 (0.852–0.985)	.019	—	—
LASRr	—	—	0.302 (0.108–0.846)	.023

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