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Abstract
Objective To evaluate the utility of two-dimensional multiplanar speckle tracking strain to assess for cardiotoxicity post allogenic bone marrow transplantation (BMT) for haematological conditions.
Methods Cross-sectional study of 120 consecutive patients post-BMT (80 pretreated with anthracyclines (BMT+AC), 40 BMT alone) recruited from a late effects haematology clinic, compared with 80 healthy controls, as part of a long-term cardiotoxicity surveillance study (mean duration from BMT to transthoracic echocardiogram 6±6 years). Left ventricular global longitudinal strain (LV GLS), global circumferential strain (LV GCS) and right ventricular free wall strain (RV FWS) were compared with traditionl parameters of function including LV ejection fraction (LVEF) and RV fractional area change.
Results LV GLS (−17.7±3.0% vs −20.2±1.9%), LV GCS (−14.7±3.5% vs −20.4±2.1%) and RV FWS (−22.6±4.7% vs −28.0±3.8%) were all significantly (p=0.001) reduced in BMT+AC versus controls, while only LV GCS (−15.9±3.5% vs −20.4±2.1%) and RV FWS (−23.9±3.5% vs −28.0±3.8%) were significantly (p=0.001) reduced in BMT group versus controls. Even in patients with LVEF >53%, ~75% of patients in both BMT groups demonstrated a reduction in GCS.
Conclusion Multiplanar strain identifies a greater number of BMT patients with subclinical LV dysfunction rather than by GLS alone, and should be evaluated as part of post-BMT patient surveillence. Reduction in GCS is possibly due to effects of preconditioning, and is not fully explained by AC exposure.
- heart failure
- echocardiography
Data availability statement
Data are available on reasonable request to the corresponding author.
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Introduction
Cancer-related mortality has decreased significantly over the past 15–20 years, with a consequent increase in cancer survivors.1 There is greater awareness of the link between chemotherapy regimens for cancer and cardiac dysfunction (cardiotoxicity). Anthracyclines (AC) are powerful cytotoxic agents, used to treat a wide spectrum of haematological malignancies2; however, significant cardiac sequelae from AC remain a problem, with 5–23% of patients developing late-onset heart failure secondary to AC-induced cardiotoxicity.3
Bone marrow transplantation (BMT) aims to reconstitute the entire haematopoietic system by transfer of blood stem cells present in the bone marrow, and is considered the treatment of choice for many haematological malignancies. It is also increasingly being used for non-haematological conditions.4 BMT may be associated with early and late toxicities directly related to chemo-radiotherapy, as well as immune complications such as graft versus host disease. Heart failure rates are quoted at 5% at 5 years after BMT, increasing to 10% at 10 years.5 Therefore, contemporary management of patients with haematological malignancies, often treated with both AC-based chemotherapy and BMT, should include careful consideration of potential cardiotoxicity, with a focus on early detection, surveillance and intervention.
Left ventricular ejection fraction (LVEF) has been the mainstay for monitoring LV dysfunction for many decades. Left ventricular (LV) global longitudinal strain (GLS) using two-dimensional (2D) echocardiography is a well-validated, semi-automated technique that measures longitudinal myocardial contractile function, and is more sensitive than LVEF for identification of subclinical LV dysfunction.6 However, little is known about alterations in multiplanar LV strain (including global circumferential strain (GCS)) and RV strain.
We have previously reported that subclinical biventricular dysfunction occurs post-BMT+AC therapy, and can be detected using strain measurements, evident in 28% of patients as reduced GLS and in 52% as reduced right ventricle free wall strain (RV FWS), despite preserved conventional LV and RV function measures.7 The current study additionally evaluates the utility of multiplanar strain analysis, including GLS and GCS, as markers of cardiac dysfunction on an expanded cohort.
Methods
Our hospital is a major tertiary referral centre for BMT and performs ~90 transplants per year. This study was a retrospective cross-sectional study to assess for cardiotoxicity within this unique and vulnerable population and to investigate the utility of novel strain imaging. One hundred twenty BMT patients, who had a routine surveillance transthoracic echocardiogram (TTE) between November 2016 and January 2020, were recruited from the haematology late effects BMT clinic. No patients were on cardiac medications at the time of their TTE. Forty patients were AC-naïve and only underwent BMT (BMT group), while the remaining 80 had received AC and subsequent BMT (BMT+AC group). The recommended cumulative AC exposure as per the European Society of Medical Oncology is defined as a doxorubicin dose >300 mg/m2.8 These BMT groups were compared with 80 age-matched healthy volunteers from our departmental database. All 120 enrolled BMT patients had LV function evaluated prior to BMT with a gated heart pool scan, in keeping with local guidelines.9
A comprehensive TTE was performed with 2D, colour and Doppler imaging, using Vivid E9 or E95 ultrasound systems (GE Vingmed, Horten, Norway), equipped with a 2.5 MHz broadband transducer.10 Biplane LV end-diastolic and end-systolic volumes were measured, and LV systolic function was evaluated by LVEF, using the Simpson’s biplane method of discs.11 LV wall thickness was measured in the parasternal long axis view at the level of the mitral leaflet tips and perpendicular to the long axis of the left ventricle. LV mass was determined from linear internal measurements using the Devereux method, and indexed to body surface area.10
Traditional measures of RV function were assessed using fractional area change (FAC),12 measured from the RV-focused view. FAC <35% was considered reduced as per European Association of Cardiovascular Imaging guidelines. Tricuspid annular plane systolic excursion was measured by placing an M-mode cursor through the tricuspid annulus and measuring the amount of longitudinal motion of the annulus at peak systole.10
Peak E and A wave velocities were measured from the apical four-chamber view with pulsed wave Doppler, with the sample volume at mitral leaflet tips. Mitral annular e’ velocity was measured using pulsed wave tissue Doppler with the sample volume placed at the lateral and septal annulus. Biplane LA volume was measured from focused four-chamber and two-chamber views, using the method of discs, and indexed to body surface area.
LV-focused and RV-focused images were obtained at high frame rates (>55 fps) for offline strain analysis. Zoomed LV apical four-chamber, two-chamber and long axis views were used for LV longitudinal strain. The strain traces were obtained through semi-automated tissue tracking. Parasternal short axis image, at the papillary muscle level, was used for circumferential strain analysis. We chose the papillary muscle level for GCS as the reliability of measurements is increased at the papillary muscle level as a circular mid-level contour is easier to acquire and to thereby obtain more reliable and reproducible GCS measurements. There is a greater chance of ‘tangential’ imaging at the base and of foreshortening at the apex.13 Radial strain was not performed due to the significant inter-observer variability. RV longitudinal free wall strain was measured from RV-focused apical view by tracing six segments including both RV free wall and septum, and calculated as the arithmetic mean of the three free wall segmental strain.10 Measurements were repeated over three cardiac cycles and an average of three measurements was used in the final statistical analysis. Strain analysis was performed using offline software (GE Echopac, Horton, Norway; V.201).
Based on the European Association of Cardiovascular Imaging and American Society of Echocardiography recommendations, normal LVEF was defined as >53%.14 We defined reduced GLS as values higher than −17%,10 while reduced GCS was defined as values higher than −18% (ie, 1 SD below the control group mean for GCS). Preserved LV function was defined as LVEF >53% and GLS better than −17%.15 We defined subclinical RV dysfunction as RV FWS worse than −25%, with preserved FAC >35%.16
In 25 randomly selected patients, strain measurements were performed by a second operator who was blinded to previous measurements, to determine inter-observer variability. The first operator performed repeated measurements on the same 25 patients 4 weeks later to ascertain intra-observer variability.
The data for this article will be shared on reasonable request to the corresponding author. It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.
Statistical analysis
Statistical analysis was performed using SPSS (IBM, V.24, Armonk, New York, USA). As variables were not normally distributed, Kruskal-Wallis test was used for analysis of more than two groups and Mann-Whitney test was used for two group analysis.
General linear models were used to assess the relationship between each of the continuous outcome variables of interest (LVEF, GLS, GCS, RV FWS, FAC) and groups, which is a three-level factor (control, BMT, BMT+AC). Each of the outcomes of interest was also dichotomised according to set cut-points (LVEF >53 and <53, GLS >17 and <17, GCS ≥18 and <18, RV FWS ≥25 and <25, FAC ≥35 and <35). Logistic regression analysis was used to assess the relationship between the dichotomised as well as continuous outcomes and groups. These were both unadjusted and adjusted, for the two-level factors (gender, smoking status and diabetes status) and the continuous covariates (age and BMI at TTE).
Unadjusted and adjusted pairwise comparisons between the three groups are presented together with appropriate 95% CIs. Mean differences are used to quantify the pairwise differences for continuous outcomes and ORs for the dichotomised outcomes. No adjustment has been made in the reported p values for multiple comparisons.
In order to minimise the potential for false positive findings, we have set a significance level of p<0.005 when interpreting the tabulated results.
Inter-observer variability was evaluated by calculation of the intraclass correlation coefficient estimates and their 95% CIs were calculated; values between 0.75 and 0.9 indicate good reliability, and values >0.90 indicate excellent reliability.17
Results
Indications for BMT are presented in table 1A. Cardiovascular risk factor profile (at time of TTE) for both BMT groups is presented in table 1B, with no significant difference between BMT groups. Demographic and clinical data are presented in table 2. All patients had normal or near-normal LVEF at baseline prior to BMT, with mean LVEF 62±7%. Only two patients received AC doses above the recommended cumulative lifetime thresholds. In the BMT+AC group, mean AC dose was 198 mg/m2 with a SD of 105 mg/m2. The mean±SD for time from BMT to TTE was 6±6 years. Traditional TTE parameters are shown in online supplemental table 1.
Supplemental material
(A) Underlying haematological condition; (B) cardiovascular risk factor profile
Demographic and clinical data
LV GLS was reduced in BMT+AC compared with BMT group (−17.7±3.0% vs −19.4±2.7%) and controls (−17.7±3.0% vs −20.2±1.9%), with non-significant difference between the BMT alone group versus controls (−19.4±2.7% vs −20.2±1.9%). However, GCS was significantly lower in both the BMT+AC (−14.7±3.5% vs −20.4±2.1%) and the BMT only (−15.9±3.5% vs −20.4±2.1%) groups as compared with controls. Similarly, RV FWS was significantly reduced in BMT (−23.9±3.5% vs −28.0±3.8%) and BMT+AC (−22.6±4.7% vs −28.0±3.8%) versus controls groups. There was no significant difference in RV FWS between the BMT groups (−23.9±3.5% vs −22.6±4.7). This is shown in table 3A–C. In the BMT+AC group, 38% demonstrated a reduction in LV GLS and 80% had a reduction in GCS. In the BMT group, 13% demonstrated a reduction in LV GLS and 71% a reduction in GCS (table 4A,B).
(A) Mean and SD for outcomes of interest; (B) unadjusted pairwise comparison between groups; (C) adjusted pairwise comparison between groups
(A) Unadjusted ORs; (B) adjusted ORs
Interestingly, in both BMT groups, GCS was significantly reduced, even in those patients with preserved longitudinal function (table 5). Scatter plot in figure 1 highlights that in patients with normal LVEF >53%, a significant proportion of both BMT and BMT+AC groups had a reduced GCS, despite their GLS being better than −17%; 59% of BMT and 36% of BMT+AC patients had evidence of reduced GCS. Figure 2 highlights that a significant proportion of patients in both BMT groups had a reduction in RV FWS, despite preserved FAC. RV dysfunction was present in 66% of BMT+AC patients and 58% of BMT patients.
Scatter plot of global circumferential strain (GCS) against global longitudinal strain (GLS); stratified by left ventricular ejection fraction (LVEF) >53% (reference line set at GCS=18 and GLS=17; strain values are represented as absolute values in the figures).
Scatter plot of right ventricle free wall strain (RV FWS) against fractional area change (FAC) (reference line set at FWS=25 and FAC=35; strain values are represented as absolute values in the figures).
Kruskal-Wallis analysis of strain parameters between patients who received only BMT, BMT and AC and controls; stratified by LVEF >53% and GLS greater than −17% (presented as median (IQR))
With regard to preconditioning, 27% of the BMT and 40% of the BMT+AC patients received myeloablative conditioning. The comparison of strain parameters between these groups is presented in online supplemental table 2A,B. Details of conditioning regimes are presented in online supplemental table 3A and common AC-containing regimes in online supplemental table 3B. Representative strain traces from a control, BMT and BMT+AC patient are shown in online supplemental figure 1.
Supplemental material
Inter-observer and intra-observer variability
The ICC for inter-observer GLS was 0.85 (95% CI 0.78 to 0.96, p=0.001) and for GCS was 0.83 (95% CI 0.75 to 0.95, p=0.001), which denotes good reproducibility. The ICC for inter-observer RV FWS was 0.91 (95% CI 0.71 to 0.98, p=0.001), which denotes excellent reproducibility. The ICC for intra-observer GLS was 0.94 (95% CI 0.86 to 0.97, p=0.001), for GCS was 0.93 (95% CI 0.83 to 0.96, p=0.001) and for RV FWS was 0.92 (95% CI 0.88 to 0.98, p=0.001), which denotes excellent reproducibility.
Discussion
This study demonstrates biventricular subclinical cardiac dysfunction, remote to BMT, using multiplanar strain by 2D speckle tracking echocardiography. Our results expand on our previous work, highlighting some novel findings:
LV GCS was significantly reduced in BMT patients, irrespective of prior AC, and is likely due to preconditioning (myeloablative or reduced intensity). This is highlighted in our graphical abstract (figure 3). In patients who received reduced intensity preconditioning, a potentially additive effect of AC was noted with worse LV GLS, GCS and RV FWS.
As expected, once LVEF was reduced (ie <53%), there was a significant reduction in both GLS and GCS, and likely represents a lost opportunity for early intervention.
While subclinical LV dysfunction has hitherto been evaluated by GLS, we demonstrate significant reduction in GCS and RV FWS despite preserved LV GLS in BMT patients, even in the absence of AC therapy.
Utility of GCS in diagnosing sub-clinical LV dysfunction. BMT, bone marrow transplantation; GCS, global circumferential strain; GLS, global longitudinal strain; LVEF, left ventricular ejection fraction.
There are several definitions of cardiotoxicity, without consensus for a single definition. The most commonly used definition is >5% LVEF reduction from baseline in symptomatic patients (or >10% reduction in asymptomatic patients) to an LVEF <53%.14 However, LVEF measurement is subject to inter-observer variability of up to 10%, which is similar to the thresholds used to define cardiotoxicity.18 The 2D speckle tracking strain is more sensitive than LVEF, eliminating to a degree the effects of loading, which compromise traditional LVEF measurement. LV GLS is an independent predictor of cardiac mortality and major adverse cardiac events, with prognostic value superior to LVEF demonstrated in non-cancer populations. It is also an effective diagnostic tool for monitoring subclinical LV dysfunction in patients with breast cancer receiving chemotherapy.14
The left ventricle has three distinct myocardial layers: subepicardial, where the fibres are aligned obliquely; mid-myocardial, where the fibres are aligned circumferentially and subendocardial where the fibres are aligned longitudinally. Longitudinal subendocardial fibres largely contribute to GLS and are more susceptible to injury from AC exposure.19 Subepicardial oblique fibres largely contribute to GCS,20 and from our results, are potentially affected by preconditioning therapy. Transmural injury results in involvement of subendocardial and subepicardial layers with reduced GLS and GCS and associated reduction in LVEF, as was evident in the subgroup of BMT patients with LVEF <53%. The mean GLS and GCS values in our control group were comparable to results from a recent meta-analysis.21
AC cause generalised myocardial injury, with likely alterations in both LV GLS and GCS. AC cardiotoxicity involves multiple complex mechanisms. The oxidative stress hypothesis is one of the commonly accepted cellular mechanisms for cardiotoxicity. AC may irreversibly disturb energy production in cardiomyocytes and damage several major structural proteins such as titin and dystrophin, thus interfering with their ability to induce adequate myocardial contraction. Late onset cardiotoxicity can develop years after AC exposure, and is the most common form of AC-induced cardiotoxicity related to irreversible cardiomyocyte loss.22
GLS is the most used and reported strain parameter, mainly due to its reproducibility. However, in late survivors of cancer, measures of GCS were consistently abnormal, even in the context of normal LVEF, but its clinical value in predicting subsequent ventricular dysfunction or heart failure has not been explored.18 Recent studies demonstrate that AC-related cardiotoxicity in patients with haemtalogical malignancies, are associated with reduction in GLS and GCS.23 Paraskevaidis et al 24 reported an early (at 1 year) significant reduction in GLS in BMT patients with prior exposure to AC; however, although GCS was decreased, this failed to reach statistical significance.
We observed a decrease in GCS in both the BMT and BMT+AC groups. We propose that this might be related to the conditioning regime that all BMT patients receive prior. Conditioning regimes can either be myeloablative or reduced intensity (RIC). Myeloablative conditioning usually involves total body irradiation and/or alkylating agents while reduced intensity conditioning regimens vary widely in intensity, most frequently employing fludarabine and an alkylating agent sometimes with a reduced dose of total body irradiation.25 There is increasing evidence that the use of these non-AC agents, such as cyclophosphamide, busulfan and melphalan, are also associated with cardiotoxicity.26 27 There appears to be an additive decrease in GCS with a reduction in GLS in the BMT+AC in patients who had received RIC (online supplemental table 2B), suggestive of interactions between the various treatments that such patients would receive, emphasising the importance of cardiac surveillance.
Historically, RV function evalaution by echocardiography was qualitative, and considered less relevant than LV function. Strain analysis has permitted quantitative evaluation of RV function. In our cohort, a higher incidence of subclinical RV than LV dysfunction was detected using strain analysis. The RV is comprised predominantly of longitudinal muscle fibres; therefore, RV longitudinal strain analysis may improve sensitivity in screening protocols for cardiotoxicity.28 Moreover, the thin walled right ventricle, working upstream from a relatively low-pressure pulmonary circulation, has less compensatory reserve, and could be affected more than the thicker walled left ventricle. Reports of paediatric patients receiving ACs, using tissue Doppler strain, have shown reduced RV strain,29 demonstrating that cardiotoxic effects are not limited to the left ventricle.
Limitations of this study are its cross-sectional nature with variable follow-up with TTE following BMT; thus, serial measurements were unavailable to correlate changes within individual patients. In this group of patients, biomarker data were unavailable. Although the sample size was relatively small, this represents a specialised group of patients from a single centre; given small subgroups for analysis of preconditioning therapies, beta errors may occur. The occurrence of cardiotoxicity can be accelerated on a background of traditional risk factors and we accept this as a possible confounder.20 Although at baseline LVEF was ascertained by GHPS (as per local BMT guidelines), our group has shown good correlation between LVEF measurements using GHPS and TTE.30 Our study provides new insights, and is a ‘proof-of-concept’ study, demonstrating multiplanar subclinical cardiac dysfunction related to BMT. Given that this was a cross-sectional study, we do not have prospective data on related adverse outcomes. Future studies following larger patient groups longitudinally are required to evaluate the benefit from initiation of cardioprotective medical therapy in those with subclinical biventricular dysfunction. In line with evolving guidelines, future studies could make use of three-dimensional datasets.31
Conclusion
Evaluation of biventricular function using multiplanar strain demonstrates subclinical dysfunction, despite preserved traditional parameters including LVEF and RV FAC; future studies will need to evaluate the benefit of cardioprotective therapy in such instances. GLS and GCS were significantly decreased in BMT patients with prior exposure to AC. However, reduction in GCS was noted even in BMT patients without prior AC exposure, and may be secondary to cardiotoxic effects from non-AC agents used in pretransplant conditioning regimes. Thus in addition to monitoring GLS, we propose that GCS and RV FWS should be considered for monitoring of BMT patients for assessment of subclinical LV dysfunction.
Key messages
What is already known on this subject?
Left ventricular (LV) global longitudinal strain (GLS) using two-dimensional echocardiography is a well-validated, semi-automated technique that measures longitudinal myocardial contractile function.
GLS is more sensitive as compared with left ventricle ejection fraction (LVEF) for identification of subclinical LV function.
However, little is known about alterations in global circumferential strain (GCS) or right ventricular (RV) GLS.
What might this study add?
Patients who undergo bone marrow transplant (BMT) and also receive anthracyclines, develop reduction in multiplanar (GLS and GCS) strain, despite preserved LVEF.
GCS was also reduced in patient who underwent BMT alone and hence may be consequent to preconditioning therapy.
RV dysfunction identified by reduced RV free wall strain (FWS) confirms the systemic and hence generalised cardiotoxic effects of anthracyclines and preconditioning chemotherapy regimes used in patients undergoing BMT.
How might this impact on clinical practice?
We propose that GCS and RV FWS should be considered as additional markers of cardiotoxicity, in addition to GLS in BMT patients.
Comprehensive strain evaluation including LV GLS, LV GCS and RV FWS should be incorporated into the routine cardiac surveillance regimes for BMT patients, to improve early detection of subclinical cardiac dysfunction.
This study highlights the need for close monitoring during the long-term follow-up of BMT patients, and to consider early commencement of cardioprotective therapy.
Data availability statement
Data are available on reasonable request to the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
Ethics approval was provided by the Western Sydney Local Health District ethics committee (HREC No. 180413-5582).
Acknowledgments
We would like to acknowledge the assistance of Dr Karen Byth with the statistical analysis.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors TD, MA, DG and LT: conceived the study. TD, PE, PG, SM, LS, MH, PB, SP, MA and LT: data collection and analysis. TD, PE, PG, MA and LT: analysed and interpreted the data. TD, PE, JC, MA and LT: drafted the initial manuscript. TD, PE, PG, SM, LS, MH, PB, SP, JC, MA, DG and LT: reviewed and edited the manuscript. All authors provided final approval.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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