Methods

The study cohort consisted of patients enrolled in a prospective observational study designed to determine predictors of postinfarction heart failure. All patients presenting to an intensive coronary care unit with AMI were eligible for entry into the study if they had a diagnosis of AMI.

Excluded were patients (1) with previously known AF or atrial flutter; (2) ≤50 years of age to minimize influence of age on transmitral flow velocity; (3) with technically limited Doppler echocardiograms and with sinus tachycardia and/or first-degree atrioventricular block resulting in partial fusion of early and late transmitral velocities of mitral inflow, ventricular pacing, and other arrhythmias; (4) with moderate or severe mitral regurgitation to avoid effects of mitral regurgitation on E-wave velocity and other Doppler parameters of filling pressures; and (5) with other significant mitral valve disease that interferes with appropriate evaluation of diastolic function (e.g., mitral stenosis). The investigational review committee on human research approved the study protocol.

Echocardiography was performed during patients’ hospital stay after a median of 2 days from admission (25th to 75th percentiles 1 to 3 days). Early and late transmitral velocities of mitral inflow, their ratio, and E-wave deceleration time were measured from the apical window using pulse-wave Doppler with the sample volume placed at the tips of the mitral leaflets during diastole. RFP was defined based on previously published criteria in patients with AMI as presence of ratio of early to late transmitral velocity ratio >1.5 and/or E-wave deceleration time <130 ms.

LV ejection fraction (LVEF) was classified as normal (≥55%), mildly decreased (45% to 54%), moderately decreased (30% to 44%), and severely decreased (<30%). LA dimensions were obtained using M-mode echocardiography guided by 2-dimensional imaging.

Diagnosis of AF was based on electrocardiographic tracing in all cases. AF was defined as absence of P waves, coarse or fine fibrillatory waves, and irregular RR intervals. New-onset AF was defined as AF detected on electrocardiogram during the follow-up period in a patient without a history of persistent or paroxysmal AF or atrial flutter.

The primary outcome of interest was development of new-onset AF during a follow-up period of 6 months. Transient postoperative AF, occurring as an isolated episode within 1 month after bypass surgery, was not considered as an outcome event. After hospital discharge, ascertainment of AF was accomplished through review of medical records and electrocardiographic tracings of each patient.

Continuous variables are presented as mean ± SD or median (25th and 75th percentiles) and categorical variables as number and percentage. Baseline characteristics of groups were compared using unpaired t test for continuous variables and by chi-square statistic for categorical variables.

Kaplan–Meier plots were used to illustrate crude cumulative incidence of new-onset AF. Univariable and multivariable Cox proportional hazard models were constructed to examine the relation between clinical and echocardiographic variables and occurrence of a first episode of AF. The following variables were considered in the multivariate procedure: age, gender, previous infarction, history of diabetes, history of hypertension, smoking, estimated glomerular filtration rate, Killip class on admission, ST-segment elevation infarction, anterior location of infarction, coronary revascularization, LVEF, LA size, and RFP. LVEF was categorized as preserved (≥45%) or decreased (<45%) and LA dimension as below (≤4.0 cm) or above (>4.0 cm) the median value. Variables demonstrating an association with AF on univariate analysis at a p value <0.2 were used in stepwise Cox regression with backward elimination variable selection.

We assessed whether the relation between LVEF and AF varied according to RFP status using formal interaction testing within the Cox regression model by incorporating terms for the main effect of LVEF, main effect of RFP, and interaction between LVEF and RFP. The impact of concomitant RFP on risk of AF was subsequently analyzed in subgroups of patients with preserved (≥45%) and decreased (<45%) LVEF.

The relation between early/late transmitral velocity and deceleration time as continuous variables and AF were also assessed through use of cubic spline functions that allowed us to explore nonlinear relations between indexes of diastolic function and AF in a regression model. Knots were placed at 0.5, 1.0, 1.5, 2.0, and 2.5 for early/late transmitral velocity and at 130, 160, 200, and 240 for deceleration time. Differences were considered statistically significant at a 2-sided p value <0.05. Statistical analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, Illinois) and STATA 10 (STATA Corporation, College Station, Texas).

Results

From July 2001 through June 2008, 1,920 patients without previous AF were recruited into the study. Patients were excluded because of age ≤50 years (n = 410), moderate or severe mitral regurgitation (n = 150), and echocardiograms in which interpretation of diastolic function was unreliable (n = 191). The remaining 1,169 patients constituted the study population.

Patients were followed for 6 months after study entry. During follow-up, 110 patients (9.4%) developed a first episode of AF. Clinical characteristics of patients according to presence or absence of AF are listed in Table 1 . Patients who developed AF during hospital course were older, had higher prevalence of hypertension and lower glomerular filtration rate, and presented with higher Killip class.

Echocardiographic parameters of patients with and without AF are listed in Table 2 . Patients who developed AF were more likely to have larger LA dimension, larger LV dimensions, lower LVEF, and higher tricuspid regurgitation velocity. Patients with new-onset AF had higher mitral early/late transmitral velocity ratios and lower E-wave deceleration times. RFP was present in 185 patients (15.8%), with higher frequency in patients with AF.

During the follow-up period, new-onset AF occurred in 36 of 185 patients with RFP (19.6%) and 74 of 984 patients (7.5%) without RFP. Median time for first AF episode was 2 days (25th to 75th percentile range 1 to 5 days). Kaplan–Meier curves demonstrated that the cumulative incidence of new-onset AF was markedly higher in patients with RFP, with most AF events occurring in the first 2 months after infarction ( Figure 1 ).

Kaplan–Meier curves showing cumulative incidence of atrial fibrillation according to presence or absence of restrictive filling pattern (p <0.0001, log-rank test).

In a univariable Cox regression model, the hazard ratio for new-onset AF was 2.72 in patients with RFP compared to patients without RFP (95% confidence interval 1.83 to 4.05, p <0.0001). Other univariable predictors of new-onset AF included age, estimated glomerular filtration rate, Killip class >I, enlarged left atrium, decreased LVEF, higher mitral early/late transmitral velocity ratio, and lower deceleration time ( Table 3 ). When cubic spline regression was used to explore the unadjusted association between early/late transmitral velocity and AF, we observed an inverted U-shaped relation but with an approximately linear relation for early/late transmitral velocity ratio >1.3 and deceleration time <150 ms and risk for AF ( Figure 2 ).

Spline function graph of unadjusted relation between early/late transmitral velocity (E/A) ratio (A) and deceleration time (B) to atrial fibrillation during 6-month follow-up. Restricted cubic splines (lines) show the shape of the relation curve for atrial fibrillation according to indexes of diastolic function on a continuous basis.

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