Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models

Abstract

Background: Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension.

Methods and results: From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ², 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics.

Conclusions: RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.

Keywords: echocardiography; heart failure; patient outcome assessment; pulmonary hypertension; right ventricular dysfunction; risk assessment; ventricular remodeling.

Figure 1

Illustration of measurements of selected right heart metrics in end-diastole (left) and end-systole (right). Right ventricular end-systolic remodeling index (RVESRI) represents a simple ratio of end-systolic lateral length to septal height (representing RV longitudinal length measured straight from the septal tricuspid annulus point to the RV insertion on the interventricular septum). RA: right atrium;; RVEDA: RV end-diastolic area; RVESA: end-systolic area; TAPSE: tricuspid annular plane systolic excursion. *Note the exclusion of the right atrial appendage.

Figure 2

Partial correlation diagrams of right heart metrics showing independent associations between parameters (A); section B illustrates the relationship adding NT-proBNP (B). Full lines represent significant direct correlations; dashed lines show inverse correlations. Thicker lines show higher statistical significance (p<0.001) than thinner lines. EIs: systolic eccentricity index; NT-proBNP: N-terminal pro-brain natriuretic peptide; RAP: echocardiographic-estimated right atrial pressure; RVLS: RV longitudinal strain; RVSP: right ventricular systolic pressure; TR: tricuspid regurgitation; others see Fig.1.

Figure 3

Scatterplot of right ventricular systolic pressure and end-systolic remodeling index (left) or area index (right) showing distribution of patients with and without events. The transition points in the pressure remodeling relationship defined three zones of adaptation as follows: the first was the transition between linear to curvilinear relationship (RVESRI of 1.35), the second was defined by the point when where progressive remodeling was associated with a decrease in RVSP (RVESRI of 1.7).

Figure 4

Five-year Kaplan Meier survival curves of right ventricular end-systolic remodeling index and strain for the primary combined endpoint of death, transplantation or hospitalization for acute right heart failure.

Figure 5

Validation of risk scores for prediction of outcomes in PAH. (A) Receiving operating curve for the primary endpoint at 3 years for the PHC, REVEAL, Scottish composite and Right Heart scores. (B) Kaplan Meier survival curves of the REVEAL registry risk score categories for the primary combined endpoint of death, transplantation or hospitalization for acute right heart failure. Low risk was defined by a score between 0 and 7, average if equal to 8, moderate high if equal to 9, high if equal to 10 or 11 and very high if ≥12. Patients were combined in three groups (REV1=low, REV2-3=average/moderate high and REV4-5=high/very high) instead of the five original groups in order to obtain balanced groups in terms of number of patients.

Figure 6

Incremental value of RVESRI for prediction of outcomes in PAH. (A) Chi-square of scores and RVESRI and RVLS for prediction of the primary endpoint (death, transplant or admission for heart failure) at 3 years. The Mayo Clinic variables (age, sex, RVLS, NYHA class and log NT-proBNP) were entered in the model using enter mode. The current derivation model was age, sex, RVESRI, NYHA class and log NT-proBNP. (B) Distribution of baseline RVESRI according to groups of the REVEAL scores (REV1=low, REV2-3=average/moderate high and REV4-5=high/very high). (C) Five-year Kaplan Meier survival curves according to the REVEAL Registry score groups and baseline RVESRI. Worst index was defined by RVESRI ≥1.60 (worst quartile) and best as <1.60 for REV1-3; and worst index was defined by RVESRI ≥1.45 and best as <1.45 for REV4-5 because of the small number of patients with best quartile (n=3). Similar results were obtained if using 1.60 for REV4-5.

Figure 7

Incremental value of change in RVESRI with time and evolution of RVESRI according to medication changes in patients with 1-year follow-up echocardiograms (n=203). (A) Relative change in RVESRI between baseline and 1 year following a normal distribution. (B) Five-year Kaplan Meier survival curves of RVESRI at 1 year according to change in RVESRI for the primary endpoint; improvement was defined by a decrease in RVESRI of >10%, worsening by an increase of >10% and stability otherwise. (C) Change in RVESRI at 1 year according to the REVEAL score groups (REV1=low, REV2-3=average/moderate high and REV4-5=high/very high). (D) Three-year Kaplan Meier survival curves according to the REVEAL Registry score groups and change in RVESRI. (E) Relative change in RVESRI between baseline and 1 year according to changes in therapy specific of PAH: prostanoids, endothelin receptor blockers and phosphodiesterase inhibitors.

Figure 8

Variability of measurements in patients with PAH (n=14). Variability of 2D measures obtained using 3D imaging standardization at maximal angle difference while still visualizing the tricuspid valve opening; this would represent the maximal changes obtainable while still being on axis (A), expressed as percentage of the difference between values obtained on plane with angle 2 and with angle 1 (B). Intra-, inter-observer reproducibility of RV metrics including test-retest (C). *p-values <0.05 for comparison with respective ICC of RVESRI. RVEDA: end-diastolic area; RVESA: end-systolic area; RVESRI: end-systolic remodeling index; RVFAC: fractional area change; RVLS: free-wall longitudinal strain; TAPSE: tricuspid area plane systolic excursion.