Evaluation of the Graft Mechanical Function Using Speckle-Tracking Echocardiography During the First Year After Orthotropic Heart Transplantation

Background

The cohort of survivors post orthotopic heart transplantation is constantly increasing, and the assessment of heart transplant recipients requires specific graft surveillance protocols in the immediate post-operative period, as well as in long-term follow-up, to monitor the function of the transplanted heart, specific pathologies that affect the donor heart, and complications of invasive endomyocardial biopsies (EMBs) that are routinely performed to detect acute cellular rejection (ACR) [1–4]. Echocardiography, which is the first-line noninvasive imaging tool for assessing orthotopic heart transplantation (OHT) patients, is the part of the serial functional and morphological evaluation during follow-up, especially after the recent introduction of strain imaging by speckle-tracking echocardiography for myocardial deformation analysis [5]. Early stages of rejection-related myocardial edema or fibrosis frequently affect the subendocardial muscle fibers, resulting in the deterioration of longitudinal graft function [6]. Therefore, speckle-tracking echocardiography (STE) analysis including longitudinal deformation analysis may identify minor, subtle myocardial dysfunction not detectable by standard echocardiography. Furthermore, echocardiographic examination is usually used in cases of suspected ACR despite negative histological findings due to sampling errors in part related to the nonhomogeneous nature of rejection [7,8]; it is also used to monitor cardiac function during biopsy-proven ACR episodes [9,10]. In a more recent meta-analysis, no single conventional echo-parameter, including left ventricular ejection fraction (LVEF) or tissue Doppler imaging (TDI)-derived measurements, could be recommended as an alternative to EMB for acute rejection diagnosis [11]. Monitoring of myocardial deformation with the measurement of LV global longitudinal strain (GLS) is known to be a more sensitive tool for diagnosing early subclinical graft dysfunction, regardless of etiology, and its evaluation may be useful when combined with EMB [12]. Previous studies found that GLS was reduced in patients with ACR requiring treatment [13,14], but little is known about the strain alterations due to the response to intense immunosuppressive therapy with intravenous steroids. However, the GLS of a transplanted heart with preserved LVEF has been reported to be lower in absolute value than that of those in the general population [15,16]. Therefore, “normal” transplanted cardiac mechanics are unknown due to the lack of appropriate cutoff values for STE parameters to detect allograft dysfunction. The existing data are currently insufficient to define the actual serial changes in LV and right ventricular (RV) strain parameters within the first year of follow-up [17], the time interval in which the risk for rejection is the highest, and to schedule repeated EMBs as the standard of care.

Thus, the aim of our study was to evaluate the alterations in LV and RV myocardial deformation during the first 12 months after heart transplantation in the context of the long-term influence of ACR episodes and to ascertain the impact of intense therapy with intravenous steroids in cases requiring ACR treatment.

Material and Methods

STUDY POPULATION:

This prospective study consisted of 50 consecutive adult heart transplant recipients admitted at the Silesian Center for Heart Diseases between January 2016 and June 2017. All the heart transplantations were performed using a bicaval technique. We excluded 5 patients (10%) who had insufficient post-transplantation imaging quality for strain analysis or an inadequate acoustic window. Consequently, our analysis cohort included 45 OHT patients.

STUDY PROTOCOL:

The patients were consecutively followed with comprehensive echocardiographic examination at baseline (within the first week), 2 weeks, and 1, 2, 3, 6, 9, and 12 months after heart transplantation. They underwent echocardiographic evaluation typically 2–3 hours before or after surveillance biopsy. As per institution policy, rejection was monitored by serial EMBs performed weekly in the first month, every 2 weeks up to the second month, at the third month and every 3 months until the end of the first year. ACR was graded using the classification of the International Society of Heart and Lung Transplantation (1R–3R). One cardiac pathologist and 1 echocardiographer who were blinded to the parallel findings performed the histopathologic and echocardiographic assessment, respectively. The patients received transplant immunosuppressive therapy according to the local protocol. Induction therapy with basiliximab was given to patients with raised pre-transplantation panel reactive anti-body levels and patients at risk of post-transplantation renal dysfunction. Maintenance therapy included tacrolimus, mycophenolate mofetil, and prednisone. In standard clinical practice, all rejections classified as grade ≥2R were treated with intravenous methylprednisolone (1 g for 3 days). To assess serial changes in strain parameters over the first year after OHT, we divided the transplanted patients into 2 groups: those with no ACRs requiring treatment (ACR-free group) and those with at least 1 episode of ACR grade ≥2R during follow-up (ACR group). Among the biopsy specimens with ACR grade ≥2R, we identified those that underwent echocardiography before the episode of rejection, at the time of pathologic diagnosis, and during therapeutic intervention with 3 days of receiving intravenous steroids. Complete strain data in the ACR group were collected for 15 patients for all 3 time points. The echocardiographic studies were performed using a Vivid E9 ultrasound system (GE Healthcare, Horten, Norway). The images were acquired using standard parasternal and apical views. The frame rate for STE was adjusted to 60–90 frames/sec. Strain and strain rate values were analyzed offline by dedicated software (EchoPAC system). The LV endocardial border was manually traced in the apical 4-chamber (4CH LS), 3-chamber (3CH LS), and 2-chamber (2CH LS) views for the calculation of longitudinal strain and strain rate. The peak values of the 6 segments in each view were averaged to provide a measurement of GLS. Longitudinal strain of RV was obtained in 6 segments in the apical 4-chamber view (RVLS) and as RV free wall longitudinal strain (RV FW) by averaging the peak longitudinal strain from 3 lateral segments. Circumferential strain and radial strain were analyzed from 6 LV segments in a short-axis view at the level of the papillary muscles. In addition, LV mechanical dyssynchrony was assessed in the longitudinal direction as the standard deviation of the time-to-peak strain (SD-TPS) of the LV lateral wall segments and the interventricular septum. Strain values are expressed as absolute numbers. The ejection fraction was calculated with the biplane Simpson’s rule. The study was in compliance with the Declaration of Helsinki and approved by our ethics committee. Written informed consent was obtained from all involved patients.

STATISTICAL ANALYSIS:

Continuous data are presented as the mean ± standard deviation (SD). We used one-way analysis of variance (ANOVA) for parametric comparisons of strain measures obtained at baseline, 2 weeks, and 1, 2, 3, 6, 9, and 12 months after OHT. Echocardiographic indices were compared between groups with or without histories of rejection at 12 months by independent samples Student’s t-test. This test was also used to compare continuous variables at different time periods: before versus during ACR grade ≥2R and rejection time versus intravenous steroid treatment of ACR. A 2-tailed P<0.05 indicated statistical significance. We used a standard statistical software package (Statistica 12, Statsoft Inc.).

RESULTS:

In the analysis cohort, we included 45 heart transplantation patients from January 2016 until June 2017. Baseline patient characteristics are shown in Table 1. A total of 220 endomyocardial biopsy specimens and echocardiograms performed 10±4 months after OHT were evaluated. Among these biopsies, treatment-requiring ACR grade 2R was detected in 30 specimens (13.6%), and 190 specimens (86.4%) showed grade 0–1R. No patients had severe (3R) rejection. Twenty-three patients (51%) had at least 1 episode of moderate ACR during follow-up, and all these episodes were asymptomatic, with LVEF remaining in the normal range. Forty patients (89%) survived the 12-month period. There were 5 deaths (11%) mainly because of severe infections, and no patient died due to rejection.

Table 2 displays changes in the myocardial strain parameters during the first year after OHT. Serial assessment of the graft mechanical function using STE shows that all LV and RV strain values were markedly attenuated immediately postoperatively in heart transplanted patients in comparison with healthy individuals [18]. GLS was impaired at baseline, remained stable but low in the first 4 weeks and improved significantly afterwards (P<0.001). We observed the same pattern in longitudinal strain values of all 3 apical views, whereas a gradual significant improvement of RV strain values, including RV LS and RV FW, appeared within the first month after OHT and lasted until the end of the first year (P<0.001), as shown in Figure 1. There were no significant differences in longitudinal systolic and diastolic strain rates between the measurements at baseline and those over time after heart transplantation. Similarly, we found that circumferential strain and radial strain did not increase significantly during follow-up. The SD-TPS did not differ significantly in serial assessments (P=0.173). In addition, there were no significant differences in strain measurements and in LV ejection fraction obtained 12 months after transplantation in t2 groups of patients: those with no treatment-requiring ACRs (ACR-free group) and those with at least 1 episode of ACR grade ≥2R (ACR group) during follow-up.

As expected, the cases of biopsy-proven ACR grade 2R were associated with marked reductions in GLS, 4-chamber longitudinal strain, systolic strain rate and RV free wall longitudinal strain (Table 3). LV mechanical dyssynchrony was quantified using SD-TPS, which increased from 44.8±8.7% before rejection to 61.5±17.9% at the time of ACR grade 2R (P=0.023). This finding showed that prolonged TPS indicates global impairment of contractile function induced by treatment-requiring ACR. Table 4 demonstrates an acute improvement of all LV and RV longitudinal strain parameters in reaction to appropriate immunosuppressive therapy for ACR in addition to no significant regression of LV mechanical dispersion. Finally, the marked differences in GLS, 4CH LS, and RV FW between the 3 time points are presented in Figure 2.

Discussion

LIMITATIONS:

We acknowledge several limitations of this study. Data were obtained from a transplantation program at a single center with a relatively small cohort of heart recipients. As a result of modern immunosuppressive therapy, there were few grade ≥2R ACR events (30 out of 220 cases). We did not evaluate the presence of humoral rejection, microvascular perfusion, or cardiac fibrosis, which could have important influences on our results. Due to the risk of sternal instability, the early postoperative echo examinations were performed in patients laying on their back, while most of the late follow-up echo studies were performed in left decubitus position. This might cause some discrepancies in the reproducibility of cross-sectional segmental visualization, thus altering strain calculation.

Conclusions

All LV and RV longitudinal myocardial strain parameters showed a gradual recovery during the first 12 months after transplantation. However, the degree of improvement measured at 12 months of follow-up was not affected by the incidence of rejection episodes. Measurements of LV and RV longitudinal strain are promising tools for the noninvasive assessment of ACR within the first year after OHT to guide the pharmacological treatment of rejection.