Predicting Survival in Repaired Tetralogy of Fallot: A Lesion-Specific and Personalized Approach

Abstract

Objectives: This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA).

Background: To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF.

Methods: Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers.

Results: The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V0₂) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value.

Conclusions: We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy.

Keywords: CMR; late gadolinium enhancement; risk stratification; sudden cardiac death; tetralogy of Fallot; ventricular tachycardia.

Graphical abstract

Figure 1

Segmental Scoring System for RV LGE Example of severe RV LGE extent in our study participant. The total RV LGE score was 12. RV-LV insertion point LGE, LV apical vent site LGE, and LV papillary muscle enhancement (asterisks) were not included in the score and were common. Patients with a total RV LGE score ≥8 were in the top quartile for RV LGE burden and were graded as severe extent. Patients with a total RV LGE score 5-7 were graded as moderate extent where score of 5 was the median. A total RV LGE score <5 was deemed as minimal or mild. The segmental system used for scoring RV LGE has been previously published. The RV is divided into 6 segments (yellow numbers 1-6). Regions of RV LGE were scored according to linear extent (0 = no enhancement, 1 = up to 2 cm, 2 = up to 3 cm, 3 = 3 or more cm in length) and number of trabeculations enhanced including the moderator band (0 = no enhancement, 1 = 1 trabeculation, 2 = 2-4). Scoring of LVLGE was performed using the universally accepted 17-segment LV model (14). Points were attributed to the proportion of LGE present in each myocardial segment, as visually judged: 0 = no LGE, 1 = up to 25%, 2 = up to 50%, 3 = up to 75%, and 4 = up to and including 100% of the myocardium enhanced. LGE = late gadolinium enhancement; LV = left ventricle; RV = right ventricle.

Figure 2

RV LGE Extent Predicts Mortality and VA Cox proportional hazard survival plots of RV LGE quartiles to predict VA (A) and all-cause mortality (B). VA = ventricular arrythmia; other abbreviations as in Figure 1.

Figure 3

Annualized All-Cause Mortality Rate According to Risk Category Risk score with weighted independent predictors of mortality. Cox proportional hazard survival plot showing percentage survival for each risk category. Corresponding risk categories, mortality rate, and annualized mortality rate.

Figure 4

Annualized Rate of VA According to Risk Category Risk score with weighted independent predictors of VA. Cox proportional hazard survival plot showing freedom from VA for each category. Corresponding risk categories, mortality rate, and annualized mortality rate. PA = pulmonary artery; RA = right atrium; RV = right ventricle; other abbreviations as in Figures 1 and 2.

Figure 5

Correspondence Between Histological Fibrosis in an Explanted Heart and the Previous In Vivo LGE CMR Patient A (left column): In vivo CMR (A1) showing LGE in the VSD patch site (yellow arrow) and RVOT (black arrows) below the PA. Postmortem macroscopic section of RV opened longitudinally (A2). VSD patch site (yellow asterisk) and RVOT (black asterisk). Microscopic examination (magnification ×200) of the RVOT (A3) confirmed the presence of extensive collagen (with Picrosirius Red stain, the collagen stained red and areas with myocardium stained yellow; magnification ×100). At higher magnification ×200, with Masson’s Trichrome stain showing areas of collagen staining blue and myocardium pale red below. Patient B (right column): LGE CMR in a patient with a childhood RVOT patch repair (B1) and RVOT LGE (black arrows). Subsequent RVOT patch surgical excision at time of elective pulmonary valve replacement confirmed macroscopic (B2 left) and microscopic (B2 right; magnification ×16) fibrosis (blue regions on the Masson’s Trichome stain) with endothelialization over the epicardial and endocardial surface of the patch seen at higher magnification (×100) in B3. CMR = cardiovascular magnetic resonance; RVOT = right ventricular outflow tract; VSD = ventricular septal defect; other abbreviations as in Figures 1, 2, and 4.

Central Illustration

Risk Score to Predict Mortality in Patients With Tetralogy of Fallot Risk score identifies contemporary adult patients with repaired tetralogy of Fallot at high annual risk of death. Abbreviations as in Figures 1, 2, and 4.