Author + information
- Received December 3, 2009
- Revision received December 16, 2010
- Accepted January 18, 2011
- Published online April 1, 2011.
- Afshin Farzaneh-Far, MD, PhD⁎,‡,
- Vignendra Ariyarajah, MD⁎,
- Chetan Shenoy, MD‡,
- Jean-Francois Dorval, MD⁎,
- Matthew Kaminski, MD⁎,
- Zelmira Curillova, MD†,
- Henry Wu, MD⁎,
- Kenneth B. Brown, MD§ and
- Raymond Y. Kwong, MD, MPH⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Raymond Y. Kwong, Brigham and Women's Hospital, Cardiovascular Division, Department of Medicine, 75 Francis Street, Boston, Massachusetts 02115
Objectives The aim of this study was to determine the prognostic value of assessing left atrial function during dobutamine stress testing.
Background Left ventricular diastolic dysfunction precedes systolic wall motion abnormalities in the ischemic cascade. Severity of left ventricular diastolic function during cardiac stress is not characterized well by current clinical imaging protocols but may be an important prognostic factor. We hypothesized that abnormal early left atrial emptying measured during dobutamine stress cardiac magnetic resonance will reflect these diastolic changes and may be associated with cardiovascular outcomes.
Methods We enrolled 122 consecutive patients referred for dobutamine stress cardiac magnetic resonance for suspected myocardial ischemia. Left atrial volumes were retrospectively measured by the biplane area-length method at left ventricular end-systole (VOLmax) and before atrial contraction (VOLbac). Left atrial passive emptying fraction defined by (VOLmax – VOLbac) × 100%/VOLmax and the absolute percent increase in left atrial passive emptying fraction during dobutamine stress (ΔLAPEF) were quantified.
Results Twenty-nine major adverse cardiac events (MACE) occurred during follow-up (median 23 months). By Kaplan-Meier analysis, patients with ΔLAPEF <10.8 (median) experienced higher incidence of MACE than did patients with a ΔLAPEF >10.8 (p = 0.004). By univariable analysis, ΔLAPEF was strongly associated with MACE (unadjusted hazard ratio for every 10% decrease = 1.56, p < 0.005). By multivariable analysis, every 10% decrease in ΔLAPEF carried a 57% increase in MACE, after adjustment to presence of myocardial ischemia and infarction.
Conclusions Reduced augmentation of left atrial passive emptying fraction during dobutamine stress demonstrated strong association with MACE. We speculate that reduced left atrial passive emptying reserve during inotropic stress may represent underlying diastolic dysfunction and warrants further investigation.
Cardiac stress testing has traditionally concentrated on the imaging and electrical properties of the left ventricle (LV). However, it is increasingly recognized that LV diastolic and systolic performance are intimately connected to left atrial (LA) function and size (1–5). For example, impaired relaxation and increased stiffness of the LV, which occur at the earliest stages of ischemia, alter LA loading conditions resulting in changes in atrial function and size (6,7). Many of these changes occur before any detectable abnormality of LV systolic function (8,9). Due to the complexity of LA function and limitations of imaging modalities in quantifying LA changes, potentially important prognostic and diagnostic information regarding the LA during stress testing has not been studied.
Left atrial function has traditionally been described as involving a “reservoir” filling phase during ventricular systole, a “conduit” or “passive” emptying phase during early diastole, and an active “contractile” pumping phase in late diastole (1). The advent of cardiac magnetic resonance (CMR) imaging with its excellent in-plane spatial resolution and reproducible scan planes allows us to assess these LA properties quantitatively during stress testing. We, therefore, hypothesized that augmentation of LA emptying function measured during staged dobutamine CMR stress testing may provide important prognostic information for predicting cardiac events in a patient cohort with clinical suspicion of coronary artery disease.
We enrolled 122 consecutive patients at Brigham and Women's Hospital, referred for CMR dobutamine stress evaluation of myocardial ischemia due to symptoms suggestive of coronary artery disease (chest pain or shortness of breath). Quantitation of LA emptying function was performed retrospectively. Patients were excluded if they had metallic implants incompatible with CMR, uncontrolled arterial hypertension (baseline systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg), more than mild mitral regurgitation, atrial fibrillation with uncontrolled ventricular response, prior adverse reaction to dobutamine, and acute myocardial infarction (MI) or sustained ventricular tachycardia <96 h prior to the study. Antianginal medications including oral beta-blockers, calcium channel blockers, and nitrates were not stopped before CMR. All patients provided a detailed history at the time of CMR. A history of high cholesterol was defined by fasting low-density lipoprotein cholesterol >100 mg/dl or current treatment with cholesterol-lowering medications. Hypertension was defined by persistent resting systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or current treatment with blood pressure-lowering medications. Significant smoking history was defined as >10 pack-years of cigarette smoking.
Twenty-three healthy volunteers (mean age 32 years, 22% women) with no cardiac history also underwent resting cine imaging, to provide comparative values in the normal population using our new method.
The local institutional review board approved the entire study protocol and clinical follow-up of patients. Informed consent was obtained from all participants immediately before performing CMR.
Dobutamine CMR was performed with a 1.5-T system (CV/i, General Electric Medical Systems, Milwaukee, Wisconsin) using a 4- to 8-element cardiac phased-array receiver coil. Noninvasive monitoring and gating for image acquisition (9500 monitor, MedRad, Warrendale, Pennsylvania) were performed continuously in all cases. Dobutamine was infused at progressive 5-min stages of 10, 20, 30, and 40 μg/kg/min via a separate intravenous line. If a resting regional wall motion abnormality was noted, dobutamine infusion was started at 5 μg/kg/min (5/10/20/30/40 μg/kg/min) in an attempt to capture the increased inotropic response of dysfunctional but viable segments. Intravenous boluses of atropine sulfate (0.25- to 0.4-mg aliquots up to a maximum total dose of 1.5 mg) were used at 30 or 40 μg/kg/min stages to augment the heart rate response. Criteria for termination of dobutamine infusion were: 1) achievement of 80% of age-predicted maximum heart rate; 2) development of new systolic wall motion abnormalities; 3) systolic hypotension (<90 mm Hg); 4) systolic hypertension (>230 mm Hg); 5) significant chest pain; and 6) complex ventricular arrhythmias. All dobutamine-CMR image acquisitions were performed with electrocardiogram gating and breath-holding. Baseline cine steady-state free precession short-axis cines were acquired to cover the entire ventricle in 8 to 14 parallel slices (8-mm thickness and 0-mm spacing, spatial resolution 1.5 × 2 mm, temporal resolution 45 to 50 ms). Cine images were obtained in 3 parallel short-axis (the base, mid, and apex) and 3 radial (3-, 4-, and 2-chamber) views at baseline and at each stress stage. With progressive heart rate increase, the views per segment were lowered (from 16 at rest to the lowest 6) to improve the temporal resolution (to ∼20 to 25 ms). During dobutamine stress, custom display permitted on-the-fly viewing of LV regional function, either by infusion stage or by slice location. A nurse controlled the dobutamine infusion and monitored the patient's symptoms and electrocardiogram continuously in the scanner room while a physician monitored the acquired images at the imaging console. Vital signs were checked at each dobutamine infusion stage.
Using a previously described inversion-recovery pulse sequence (10) (repetition time: 4.8 ms; echo time: 1.3 ms; in-plane spatial resolution between 1.5 × 1.8 mm and 1.8 × 2.1 mm), late gadolinium enhancement (LGE) images were acquired at slices matching the baseline cine slice locations about 10 to 15 min after intravenous gadolinium–diethyltriaminepentaacetic acid administration (0.15 to 0.20 mmol/kg; Magnevist, Berlex Pharmaceuticals, Wayne, New Jersey). We optimized the inversion time (200 to 300 ms) to null normal myocardium and adjusted the views per segment according to the patient's heart rate to minimize any image blurring.
Cine function analysis was performed offline with standard validated software (QMASS, Leiden, the Netherlands) (11). An experienced (level-III CMR-trained) reader manually traced the endocardial contours of the LA in all cine studies. Left atrial areas in the 4- and 2-chamber long-axis views were measured at the end of ventricular systole, just before atrial contraction, and at the end of ventricular diastole. Identification of the correct timing required careful scrolling through the cardiac cycle frame by frame. Maximum atrial volume at end-systole was determined as the frame just before mitral valve opening in early diastole. The timing of the frame before atrial contraction was determined as occurring just before the second upward movement of the mitral annulus away from the apex (the first movement occurred during early diastole). This also corresponded to the frame just before the second opening movement of the mitral valve in diastole. Minimum atrial volume at end-diastole was determined as the frame just before mitral valve closure.
By convention, the inferior LA border was defined as the plane of the mitral annulus and not the tips of the leaflets (12,13). Similarly, the atrial appendage, pulmonary veins, and recesses of the mitral valve were excluded by drawing a straight line across these structures to adjacent atrial borders. Atrial length was measured from the midpoint of the mitral annulus plane to the superior margin of the LA in both 4- and 2-chamber views. Left atrial volumes were calculated using the biplane area-length method that has been validated, by CMR, to be accurate and reproducible compared with volumetric analysis: LA volume = (Area4-chamber) × (Area2-chamber) × 0.85/atrial length (12–14). The shorter atrial length from either the 4- or 2-chamber view was used as recommended for this formula.
Left atrial volumes were calculated at the end of ventricular systole (VOLmax), just before atrial contraction (VOLbac), and at the end of ventricular diastole (VOLmin). Left atrial volume indexes were calculated by dividing each of VOLmax, VOLmin, and VOLbac by the patient's body surface area calculated by the DuBois formula. From the LA volumes, the following parameters of atrial function were calculated: 1) LA passive emptying fraction (LAPEF) = (VOLmax – VOLbac) × 100%/VOLmax; 2) LA contractile emptying fraction (LACEF) = (VOLbac – VOLmin) × 100%/VOLbac; 3) LA reservoir emptying fraction (LAREF) = (VOLmax – VOLmin) × 100%/VOLmax. For each patient, the maximum dobutamine-induced augmentation of these atrial functional parameters was calculated as the maximal increase in absolute percent from rest to stress (ΔLAPEF, ΔLACEF, and ΔLAREF, respectively) (Fig. 1). In 30 randomly selected patients, a second level-III CMR trained blinded physician measured the previously mentioned LA dimensions for assessment of interobserver variability.
LV volumes indexed to body surface area and ejection fraction were measured from the short-axis cine images using the Simpson method. LV mass was calculated by subtracting the endocardial volume from the epicardial volume at end-diastole and then multiplying by the tissue density (1.05 g/ml). The short-axis LGE imaging stack of 8 to 14 parallel slices covering the entire LV was used to assess infarct size. The endocardial and epicardial contours on these LGE images were traced manually. Using a semiautomatic detection algorithm, we applied a signal-intensity threshold of ≥2 SDs above a remote reference myocardial region on the same slice to quantify the total mass extent of any MI (15).
Wall motion was scored at each dobutamine stage on a 17-segment model using the 4-point index recommended by the American Society of Echocardiography where 1 = normal, 2 = hypokinesia, 3 = akinesia, and 4 = dyskinesia (13). Dobutamine-induced wall motion abnormality/ischemia was defined as the presence of segmental wall motion grade increment >1 during progressive dobutamine stress, except that a progression of segmental akinesia to dyskinesia was considered nonspecific. Apart from the LV apex, a myocardial segment was considered ischemic only if concordant findings were observed on both the short-axis and matching long-axis views.
After CMR, subjects were prospectively followed for a median of 23 months (range 6 to 54 months). The follow-up period was pre-determined to begin after at least 6 months had elapsed from the time of CMR. Patients were contacted once. Clinical follow-up based on a standard questionnaire was obtained from telephone interviews with the patients, relatives, physicians, or from hospital records. Survival status was obtained through a query of the National Social Security Death Index. Major adverse cardiac events (MACE) were defined as death from any cause, acute MI, unstable angina, and development or progression of heart failure. Unstable angina was defined by hospitalization because of chest pain plus either angiographic coronary stenosis of >70% or significant ischemia on noninvasive stress testing. Development or progression of heart failure was defined as either new hospitalization for heart failure or a need for heart transplantation. When more than 1 of these events occurred, the first event was used in the analysis. Patients who had not experienced a MACE but were referred to undergo coronary revascularization (percutaneous approach or coronary bypass grafting) were censored at the time of the coronary revascularization.
All continuous variables were expressed as mean ± SD. A p value of <0.05 was considered statistically significant. Baseline patient characteristics stratified by ΔLAPEF were compared using the 2-tailed t test and Fisher exact test as appropriate. Interobserver variability was analyzed using the Bland-Altman method (16). In addition, kappa values were calculated to assess interobserver agreement in categorizing LA function parameters (LAPEF, LACEF, and LAREF) as normal or abnormal. Abnormally low LA function parameters were defined as <2 SDs from the mean values from our normal population. Kaplan-Meier analyses for MACE between low and high ΔLAPEF groups were compared by the log-rank test. We fitted Cox proportional-hazards survival models to estimate the unadjusted hazard ratios (HRs) and the 95% confidence intervals (CIs) of all the variables. For multivariable regression analyses, we further assessed the association of ΔLAPEF with MACE, adjusted to a set of clinical and LV imaging predictors based on the univariable analysis. We selected the number of variables in each multivariable model to have approximately 1 variable for every 10 events, to reduce overfitting. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina). In the multivariable models, the validity of the proportional-hazards assumption was tested by including a time-dependent interaction variable for each of the predictors in each of the models (17). The global test score in SAS, based on scaled Schoenfeld residuals was used to test for presence of any time-dependent covariates in the models (18). Using this, we found no evidence of violation of the proportional hazards assumption in any of the final multivariable models.
We enrolled 122 consecutive patients of which 14 (11%) were excluded due to inability to complete the dobutamine stress test or poor image quality. Three of these 14 (21%) patients experienced MACE (1 death, 2 congestive heart failure admissions) during follow-up. The remaining 108 patients (67 men, mean age 61 ± 12 years) constituted the study cohort. Table 1 summarizes the clinical characteristics and CMR findings of the study population, stratified by median level of ΔLAPEF. In some patients, LAPEF deteriorated with stress, resulting in a negative value for ΔLAPEF. In the current study cohort, mean ΔLAPEF was 11 ± 14% (median 10.8%, interquartile range 23%, range –16% to 41%). Patients with ΔLAPEF below the median value had lower baseline LV ejection fractions at rest, larger LV end-diastolic and end-systolic volume indexes, and a trend increase in inducible wall motion deterioration during progressive dobutamine stress.
Table 2 shows resting LA volumes and LA functional parameters for the group of healthy volunteers and study patients. Bland-Altman analysis of interobserver variability for VOLmax, VOLbac, and VOLmin showed a bias (±95% limits of agreement) of 1.5 ± 7.9 ml, 1.0 ± 7.8 ml, and 3.2 ± 7.6 ml, respectively. The Bland-Altman plots showed no systematic bias (Fig. 2). In addition, kappa values were calculated to assess interobserver agreement in detecting abnormally low LA function parameters (LAPEF, LACEF, and LAREF). Abnormally low LA function parameters were defined as <2 SDs of the means of these parameters measured from the group of 30 randomly selected patients. The interobserver agreement for detection of abnormally low atrial function parameters was good (kappa = 0.75 for LAPEF, kappa = 0.84 for LACEF, and kappa = 0.86 for LAREF).
Univariable association with MACE
A total of 29 MACE (16 deaths, 3 acute MI, 7 unstable angina, and 3 congestive heart failure episodes requiring hospitalization) occurred during a median follow-up of 23 months. Figure 3 illustrates the Kaplan-Meier survival curves stratified by median ΔLAPEF. Patients with a ΔLAPEF < median experienced a worse event-free survival during the study period than did patients with a ΔLAPEF > median (p = 0.004). Table 3 lists the univariable predictors of MACE. As a continuous variable, every 10% decrease in ΔLAPEF corresponded to an increase in MACE hazards by 56%. Other significant univariable predictors of MACE included patient age and beta-blocker use, as well as the imaging variables of dobutamine-induced wall motion abnormalities, LGE, and resting LA volume at end-diastole (VOLmin). Baseline wall motion score index did not demonstrate any significant association with MACE. Both LV ejection fraction of <40% and infarct size per 10% change trended toward significance as univariable predictors of MACE (both p = 0.06 and 0.05, respectively). Mean infarct transmural extent, ΔLACEF, and ΔLAREF did not demonstrate significant prognostic association with MACE.
Multivariable association with MACE
Table 4 illustrates the multivariable analysis of MACE. After adjustment for the effects of beta-blocker use and patient age in years (the 2 strongest univariable clinical predictors of MACE), ΔLAPEF maintained a strong and independent association with MACE. Every 10% decrease in ΔLAPEF was associated with a 57% increase in MACE (p = 0.006). Another multivariable model determined the prognostic association of ΔLAPEF adjusted to the effects of dobutamine-induced wall motion abnormality and presence of LGE (the 2 strongest univariable LV imaging predictors of MACE). Adjusting to presence of myocardial scar by LGE imaging and dobutamine-induced wall motion abnormality, every 10% reduction in ΔLAPEF was associated with a 57% increase in MACE (p = 0.01). When added to the model that consisted of LGE presence and dobutamine-induced wall motion abnormality, ΔLAPEF increased the model likelihood ratio chi-square from 8.76 to 16.00 (p < 0.01). Although increase in wall motion score index (from baseline to peak dobutamine) was a univariable predictor of MACE (Table 3), it had no significant predictive value after adjustment to ΔLAPEF (Table 4). In addition, ΔLAPEF maintained a significant association with MACE even after adjustment to both presence of LGE and infarct size (adjusted HR: 1.04/10% change in ΔLAPEF, 95% CI: 1.01 to 1.08, p = 0.008). Moreover, ΔLAPEF was associated with MACE independent of the effects of resting LA size. When adjusted to VOLmin, ΔLAPEF still provided incremental association with MACE (adjusted HR: 1.05/10% change in ΔLAPEF, 95% CI: 1.02 to 1.08, p = 0.003).
Prognostic association of ΔLAPEF in patients without regional wall motion deterioration during progressive dobutamine stress
Twenty-eight patients (26%) of the cohort demonstrated deterioration of regional LV wall motion that is indicative of myocardial ischemia, whereas the other 80 patients did not. Out of the 80 patients who had no evidence of ischemia, 16 experienced MACE in the follow-up period (including 7 deaths, 2 acute MIs, 6 unstable angina hospitalizations, and 1 heart failure hospitalization). In these patients, ΔLAPEF < median is strongly associated with MACE despite a lack of evidence for myocardial ischemia by wall motion abnormality. In this subset of patients, every 10% reduction of ΔLAPEF was associated with a 56% increase in MACE hazards (HR: 1.56, 95% CI: 1.06 to 2.30, chi-square likelihood ratio: 5.03).
To our knowledge, this is the first study to quantitatively evaluate LA emptying function during cardiac stress testing. Our data indicate that reduced augmentation of passive LA emptying fraction (ΔLAPEF) is a predictor of cardiac events. Every 10% decrease in ΔLAPEF is associated with a 57% increase in MACE, after adjusting for presence of inducible ischemia and myocardial scar. We have provided preliminary data from a pilot clinical cohort with relatively few adverse events and consequently limited multivariable adjustments were possible. Nevertheless, these findings are suggestive of a close inter-relationship between stress-induced LA and diastolic dysfunction with adverse outcomes.
LA function and ventricular performance
The close coupling between LV and LA function highlights the somewhat artificial distinction made between these 2 properties (1–5). During LV systole, the downward movement of the mitral annulus stretches the atria so that atrial and ventricular volumes reciprocate. This is also the case during early diastolic LA emptying, when ventricular relaxation and elastic recoil move the mitral annulus upward, significantly contributing to LV filling. This has led some to suggest that these LA functional properties should really be thought of as LV properties (19).
Atrial function and MACE
Kizer et al. (20) showed that LA pumping function at rest can predict cardiac events in a population-based cohort. We have shown that an inability to augment LA passive emptying fraction with stress is a predictor of poor outcome. Presumably, these patients are unable to increase early diastolic filling by improving active relaxation or ventricular suction. Thus, augmentation of LA passive function may be a measure of early diastolic functional reserve. We have shown that ischemia as detected by new or worsening LV wall motion abnormalities with stress was not an independent predictor of MACE when adjusted for the effects of LA passive functional reserve. This maybe because diastolic abnormalities responsible for failure of LA passive function augmentation precede obvious systolic wall motion deterioration as described in the concept of the ischemic cascade (8,9,21).
LA function during ischemia
A significant body of animal and human experimental data has shown that during an ischemic insult, changes in diastolic LV function occur before any changes in systolic wall motion (6–9,21). Thus, relying on detection of systolic wall motion abnormalities alone may result in missing some patients with early ischemia. Similarly, changes in LA function during angioplasty have been shown to precede changes in LV systolic function (7).
There are several possible mechanisms by which ischemia leads to abnormalities of ventricular filling early in diastole and thus to a diminution of LA passive functional reserve (8,22): 1) myocardial relaxation is an exquisitely energy-dependent process and highly sensitive to the effects of ischemia, because adenosine triphosphate hydrolysis is needed to release tightly bound actin-myosin bonds and for calcium reuptake into the sarcoplasmic reticulum; and 2) subendocardial longitudinal fibers are particularly sensitive to ischemia. This leads to uncoordinated or asynchronous relaxation between circumferential and longitudinal fibers in ischemic areas, as well as a reduction in longitudinal contractile function that may not be initially detectable but which could lead to diminished ventricular suction. It should be noted that classical markers of LV diastolic function were not measured in the current study. It would be of interest to know if LA functional parameters (such as ΔLAPEF) are more sensitive to LV ischemia than classical diastolic markers.
Relative prognostic importance of atrial reservoir, passive, and pump functions
Our study did not show a significant prognostic effect of changes in atrial reservoir or contractile function on future cardiac events. It has been shown that transient ischemia tends to increase atrial contractile function (the atrial booster pump), mildly decrease atrial reservoir function, and profoundly decrease atrial passive function (6). This suggests that our finding of prognostic significance only with atrial passive function may be because it is the most sensitive marker of ischemia due to the particular energy dependence of early myocardial relaxation as opposed to other aspects of diastolic function.
Given the small study size, the current multivariable models were limited to a few selected clinical and LV imaging variables. Thus, we were unable to estimate the association of ΔLAPEF with MACE when simultaneously adjusted to all possible predictors. Also given the small study size, the possibility of selection bias must be kept in mind, particularly given the relatively high event rates that were observed in those with no stress-induced wall motion abnormalities. At the time of this study, stress CMR was not the first line stress test at our institution. It is therefore likely that there was selection bias present with predominantly more complex and sicker patients referred for this examination. The risk associated with a negative test is highly dependent on the underlying population risk. For example, others have found MACE rates in high risk patients with LV dysfunction and a negative dobutamine stress CMR of around 30% at 24 months (23). Thus although our event rates are high in the negative stress test group, this is likely a reflection of the sick population studied.
Finally, although the LA volumes measured in our normal subjects are high compared with those reported in the echocardiographic literature, they are similar to recently reported CMR reference ranges (40.0 ± 6.7 ml/m2) (24,25).
Augmentation of LA passive emptying fraction during dobutamine stress, quantified by CMR, is a predictor of cardiovascular prognosis, independent of major clinical or LV imaging predictors. Our findings are consistent with a close relationship between LA passive emptying function and LV diastolic dysfunction. However, the mechanisms linking stress-induced changes in LA function with adverse outcomes require further study.
The authors have reported that they have no relationships to disclose.
- Abbreviations and acronyms
- cardiac magnetic resonance
- left atrium/atrial
- left atrial passive emptying fraction
- absolute percent increase in left atrial passive emptying fraction
- left atrial reservoir emptying fraction
- left ventricle/ventricular
- major adverse cardiac events
- left atrial volume before atrial contraction
- left atrial volume at end-systole
- left atrial volume at end-diastole
- Received December 3, 2009.
- Revision received December 16, 2010.
- Accepted January 18, 2011.
- American College of Cardiology Foundation
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