Left ventricular strain and fibrosis in adults with repaired tetralogy of Fallot: A case-control study
de Alba CG, Khan A, Woods P, Broberg CS.
Int J Cardiol. 2020 Sep 1:S0167-5273(20)33719-0. doi: 10.1016/j.ijcard.2020.08.092. Online ahead of print.
Take Home Points:
- Left ventricular dysfunction is an expected complication after rTOF and has significant prognostic implications.
- CMR can provide quantification of both myocardial strain analysis and diffuse fibrosis, both of which have associations with other clinical variables and outcomes:
- LVECV (left ventricular myocardial extracellular volume) was the only univariate predictor of arrhythmia.
- All 2D strains were significantly associated with hospitalization and death.
- However, no association was seen between global systolic strain and LV-ECV.
- The study suggests these metrics are reflective of different pathologic processes and related to different types of outcome.
Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch: The long-term follow-up of repaired tetralogy of Fallot (rTOF) is typically focused on RV systolic and diastolic function. However, the LV is also a factor contributing to decreased exercise capacity, ventricular arrhythmias, and mortality. A plausible explanation is that moderate to severe pulmonary insufficiency creates chronic RV volume load which drives RV dilation and increased RV wall stress, which in turn lead to LV dysfunction via ventricular-ventricular interactions.
Myocardial extracellular volume (ECV), a surrogate of diffuse interstitial myocardial fibrosis, can be evaluated by T1 mapping. Increased myocardial fibrosis has been found in patients with TOF, even at a young age and has been associated with abnormal LV mechanics. In addition, CMR-based feature tracking (CMR-FT) assessment of myocardial strain can be used as a measure of both global and regional myocardial function. Its use in rTOF remains limited. Because both LV-ECV and strain measures reflect LV myocardial change, and because both have limited association with clinical endpoints, the study postulated that the two measures would be associated with one another.
The primary aim of the study was to determine whether LV myocardial fibrosis measured by T1 mapping is associated with LV systolic strain measured by CMR-FT. The secondary aim was to determine the association between LV systolic strain and LV-ECV with three major clinical outcomes: death, arrhythmia and hospitalization for heart failure.
Patients and Methods:
CMR studies from adults with rTOF and healthy subjects without known cardiovascular disease were retrospectively reanalyzed. Strain analysis was done using the tissue tracking algorithm in Circle Cardiovascular Imaging Software (Version 5.6.8 Calgary, Canada). LV-ECV was quantified using a single short axis Look-Locker sequence at the midmyocardium, for which signal intensity vs. time curves were plotted for myocardium and blood pool before and several time points up to 25 min after contrast administration.
New atrial arrhythmia was defined as a sustained atrial arrhythmia, either symptomatic or requiring treatment. Ventricular arrhythmia was defined as non-sustained ventricular tachycardia lasting 30 beats, or any symptomatic ventricular arrhythmia requiring treatment. Non-elective hospitalizations for heart failure symptoms or elevated BNP requiring diuresis were considered.
The initial study cohort consisted of 52 rTOF subjects. Upon review, four rTOF subjects did not have adequate quality cine imaging in all views, either because of respiratory artifact or gating issues, to make accurate strain quantifications and were not included. The remaining 48 rTOF subjects constituted our patient cohort (age 40.5, SD = 14.3 years, 42% female) with 20 controls (age 39.4, SD = 11.9, 45% female). Group comparisons are presented in Table 1. As expected, the groups also differed by LV systolic volume, LV ejection fraction, left atrial volume, and RV size and function.
Global circumferential strain (GCS), both 2 dimensional (2D) and 3 dimensional (3D) were lower in rTOF subjects (p ≤0.0001 for both, Table 1). Global longitudinal strain (GLS) both by 2D and 3D were also significantly lower in rTOF subjects (p ≤0.0001 for both). Global 2D radial strain (GRS) was lower in rTOF subjects compared to controls (Table 1).
LVEF and LVESV were both significantly associated with all global (2D and 3D) peak systolic strain values. No significant association was seen between strain and right ventricular volumetric parameters. There was a weak association between all 2D strain parameters and RVEF, however this was not significant after adjusting for multiple comparisons. There was no association between global systolic strain and LV-ECV.
Kaplan-Meier plots for arrhythmia free survival and death (Figure. 1), for both LV-ECV and GLS are shown. By Cox-regression analysis, LVECV was the only univariate predictor of arrhythmia. All 2D strains were significantly associated with hospitalization and death (univariate).
LV-ECV was also a significant univariate predictor of both hospitalization and death. Based on limited multivariate models, the only consistent independent predictor of arrhythmia was LV-ECV (HR=1.198, 95% CI 1.04–1.38, p=0.013). GLS was the only consistent multivariate predictor of hospitalization (HR = 1.48, 95% CI 1.11–1.96, p = 0.007) and of death (HR = 1.63, 95% CI 1.16–2.30, p = 0.005).
ECV and myocardial strain have gained wide interest in the last decade as tools for myocardial assessment. Our study confirms that both LV-ECV and global systolic strain are abnormal compared to controls and are associated with cardiac chamber size and function and clinical outcome. Previous studies have shown associations between these measures and clinical events such as arrhythmias, LV systolic and diastolic dysfunction and death, though with some mixed results. Therefore, strain and fibrosis both appear to demonstrate different myocardial characteristics that may both play a role in the natural history of rTOF.
This study explored the relationship between fibrosis and strain quantified from the same imaging examination. It included a wide range of strain parameters and found no association between these two types of metrics. Our results differ from previous investigators who found that T1-derived markers for myocardial fibrosis in rTOF patients were moderately related to peak LV radial strain and weakly associated to circumferential strain.
Interestingly, that study was performed in a younger population than ours (mean age 26 ± 11 years) who had a mean lower LV-ECV overall (24.5 ± 5.1). The varying findings may also reflect different strain analysis algorithms inherent in different commercially available analysis modules.
While both LV strain abnormalities and fibrosis are present in rTOF, they are associated with different types of clinical outcome, and not to each other. The findings suggest that these measures reflect different long-term adverse adaptations to abnormal hemodynamics.
- Strain quantification methods and algorithms differ between software vendors, and strain values between echo and CMR are not comparable.
- The study is small with low number of outcomes. A larger cohort would allow stronger confirmation of the findings. Multivariate regression was limited given the low number of clinical outcomes.