In pediatric heart transplant recipients, elevated pulmonary capillary wedge pressure (PCWP) is associated with rejection and coronary artery vasculopathy. This study aimed to evaluate which echocardiographic parameters track changes in PCWP and predict adverse outcomes (rejection or coronary artery vasculopathy). This prospective single-center study enrolled 49 patients (median 11.4 years old, interquartile range 7.4 to 16.5) at time of cardiac catheterization and echocardiography. Median follow-up was 2.4 years (range 1.2 to 3.1 years), with serial testing per clinical protocol. Ratio of early mitral inflow to annular velocity (E/E′), left atrial (LA) distensibility, peak LA systolic strain, E/left ventricular (LV) diastolic strain, and E/LV diastolic strain rate were measured from echocardiograms. Increase in PCWP ≥3 mm Hg was associated with changes in LA distensibility, E/E′, and E/LV diastolic strain, with highest area under the receiver operating characteristic curve for E/LV diastolic strain (0.76). In 9 patients who subsequently developed rejection or coronary artery vasculopathy, E/LV diastolic strain rate at baseline differed from patients without events (median 57.0 vs 43.6, p = 0.02). On serial studies, only change in LV ejection fraction differed in patients with events (median −10% vs −1%, p = 0.01); decrease in LV ejection fraction of −19% had a specificity of 100% and sensitivity of 44%. In conclusion, LV diastolic strain and strain rate measurements can track changes in PCWP and identify patients at risk for subsequent rejection or coronary artery vasculopathy. Further studies are necessary to confirm these data in a larger cohort.
In pediatric heart transplant recipients, left ventricular end-diastolic pressure (LVEDP) and its surrogate measurement, pulmonary capillary wedge pressure (PCWP), are related to rejection and transplant coronary artery disease. LVEDP is commonly estimated noninvasively by the ratio of peak mitral inflow velocity to peak early diastolic annular velocity (E/E′), but this relation is less reliable in the pediatric population, with much overlap between normal controls and patients with significant diastolic dysfunction. In the pediatric heart transplant population, left atrial (LA) measurements, such as distensibility and peak systolic strain, and the ratio of mitral inflow velocity (E) to early LV diastolic strain rate correlate with PCWP in cross-sectional studies, but longitudinal data are lacking to evaluate for changes in PCWP or prediction of adverse outcomes. This study aimed to evaluate which LA or LV measurements can track changes in PCWP and predict outcomes in this population.
Methods
Consecutive pediatric heart transplant recipients at the University of Michigan Congenital Heart Center were prospectively recruited from March 2012 to January 2014 at the time of presentation for clinically indicated right and/or left heart catheterization for biopsy or angiography and were followed through August 2015. Patients were excluded if they were >21 years old at the time of enrollment or if they had mitral stenosis, more than mild mitral regurgitation, or pulmonary venous stenosis. This study was approved by the institutional review board, and each patient and/or guardian provided informed consent.
Right-sided cardiac catheterization was performed under conscious sedation in all patients. An end-hole balloon wedge catheter was used to measure right-sided cardiac chamber pressures and placed in a wedge position to measure mean PCWP. Because patients were spontaneously breathing, PCWP was measured during exhalation and averaged over 2 to 3 respiratory cycles. In patients who underwent additional left heart catheterization, a pigtail catheter was advanced retrograde through the aortic valve to measure LVEDP, and simultaneous PCWP and LVEDP measurements were obtained. Elevated PCWP was defined as an increase of ≥3 mm Hg from the previous measurement.
Echocardiograms were performed immediately after catheterization and as clinically indicated, with a Vivid E9 (GE Ultrasound, Milwaukee, WI) machine per clinical protocol for functional analysis. Owing to workflow issues, some studies were performed with iE33 or Epiq systems (Philips, Best, the Netherlands). To minimize the risk of sedation, additional sedation medication was not given after the catheterization unless the patient could not tolerate a nonsedated echocardiogram; subjects were typically awake but calm during the echocardiogram. All echocardiographic measurements were performed by an experienced echocardiographer blinded to PCWP measurements and measurements from other echocardiograms. E/E′ ratio was measured using the average of tissue Doppler velocity samples at the medial and lateral annulus, as per American Society of Echocardiography recommendations.
LA volume was calculated by biplane area–length method from apical 4-chamber and 2-chamber views and was indexed to body surface area. Distensibility was defined as: (LA maximum volume−LA minimum volume)/(LA minimum volume). Maximum and minimum volumes were identified by the frame before mitral valve opening and the frame at mitral valve closure, respectively. Distensibility thus reflects the percentage increase in volume during ventricular systole or LA reservoir function. LV ejection fraction was measured by 5/6 area × length method, as recommended in pediatric populations.
Strain measurements were measured only for studies performed on the GE Vivid E9, because of intervendor differences in strain measurements. Median frame rate on images used for strain analysis was 74 Hz (interquartile range [IQR] 67 to 80). Peak global LA longitudinal systolic strain was measured from 4-chamber images using EchoPAC speckle tracking software (GE Ultrasound). Contours were visually evaluated for adequate tracking and adjusted as necessary. Peak global longitudinal strain was manually identified and measured at the highest point of the average strain curve, even if it occurred after aortic valve closure. To evaluate global LV relaxation, early LV diastolic strain and strain rate were measured from 4-chamber images ( Figure 1 ), and corrected for peak early mitral inflow (E/LV diastolic strain or E/LV diastolic strain rate), analogous to E/E′. Early LV diastolic strain was measured at the time of peak early LV diastolic strain rate.
Serial testing, including echocardiography and cardiac catheterization, was performed according to clinical protocol. The composite adverse outcome was new diagnosis of rejection (defined as International Society for Heart and Lung Transplantation grade ≥2/1R or hospitalization with immunosuppressive therapy started before biopsy) or coronary artery vasculopathy. Although our institution would not typically treat grade 2/1R rejection, this would lead to treatment in some centers, and echocardiographic detection of early rejection could lead to medication adjustment or change in biopsy schedule.
Descriptive data are presented as frequency with percentage for categorical variables and mean ± SD or median with IQR for continuous variables, as appropriate. Correlation between continuous variables was evaluated using Pearson or Spearman’s correlation coefficient. Among patients with subsequent increase in PCWP, change in echocardiographic variables (from the time of elevated PCWP to nearest echocardiogram without elevated PCWP) was compared with patients who had stable PCWP (using echocardiographic data from baseline and follow-up studies) using Wilcoxon rank-sum test. Similar comparison was also made between patients with and without events to identify echocardiographic predictors of the subsequent adverse event (from the last echocardiogram preceding the event), and markers at the time of the event, using 2-sample t test or Wilcoxon rank-sum test. By receiver operating characteristics (ROC) curve analysis, the area under the curve (AUC) of each echocardiographic variable was compared to determine the most predictive echocardiographic parameter for elevated PCWP or for subsequent adverse event. The optimal cutoff of the selected echocardiographic parameter was then identified as the best combination of sensitivity and specificity for significant discrimination of increased PCWP or of an adverse event from the ROC curve. To ascertain the predictive ability of the optimal cutoff, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also reported. p Values <0.05 were considered statistically significant. All analyses were performed using SAS, version 9.4 (SAS Institute, Cary, North Carolina).
Results
Of 52 consecutive patients, one patient declined consent, and one patient did not have an echocardiogram on the same day as catheterization. A total of 50 patients were thus enrolled; one patient had moderate mitral regurgitation on baseline echocardiogram and was subsequently excluded from analysis. Patient demographics and baseline characteristics are presented in Table 1 . All patients were in sinus rhythm. Median duration of follow-up was 2.4 years (range 1.2 to 3.1 years). In 26 patients with left heart catheterization, PCWP correlated closely with LVEDP ( r = 0.83, p <0.0001).
| Age at enrollment (years) | 11.4 (7.4-16.5) |
| Male sex | 30 (61%) |
| Age at transplant (years) | 5.1 (2.1-11.1) |
| Time since transplant (years) | 3.3 (0.5-8.8) |
| Type of transplant | |
| Bicaval | 39 (80%) |
| Biatrial | 7 (14%) |
| Unknown | 3 (6%) |
| Pulmonary capillary wedge pressure (mmHg) | 10 (8-13) |
| Coronary vasculopathy | 4/27 (15%) |
| International Society for Heart and Lung Transplantation Rejection Grade | |
| 0 | 27 (55%) |
| 1a | 6 (12%) |
| 1b | 1 (2%) |
| 2 | 2 (4%) |
| Unknown | 13 (27%) |
| Ratio of mitral inflow to average annular velocity (E/E’) | 8.2 (7.0-10.2) |
| Left ventricular ejection fraction (%) | 60.5 ± 7.4 |
PCWP increased in 29 of 46 patients (63%) with serial cardiac catheterizations and paired echocardiograms with a median of 1.3 years (IQR 1.0 to 2.1) apart. In this subset, PCWP increased from 9.0 ± 3.3 mm Hg to 15.9 ± 5.1 mm Hg; 25 of 29 patients (86%) had PCWP ≥12 mm Hg at follow-up. Increase in PCWP was associated with changes in LA distensibility, E/E′, and E/LV diastolic strain ( Figure 2 ). From the ROC curve analysis, change in E/LV diastolic strain was the most predictive parameter for increased PCWP ( Figure 3 ). Changes in E/E′ and LA distensibility had slightly lower AUCs (0.75 and 0.71, respectively). Change in E/LV diastolic strain of −1.3 showed best discrimination between patients with and without increase in PCWP, with 93% specificity, 63% sensitivity, 92% PPV, and 67% NPV.
