Effect of sodium-glucose cotransporter 2 inhibitors on ventricular function in systemic right ventricular failure

Abstract

Background: Systemic right ventricle (sRV) patients are at an increased risk of developing heart failure. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) could be a valuable treatment option. This study investigated the changes in ventricular function in sRV failure patients in the first year after starting SGLT2i.

Methods: Adult sRV patients from the international, real-world ACHIEVE-SGLT2i registry were included if they had a clinical diagnosis of sRV failure, a transthoracic echocardiogram before starting SGLT2i, and at least one in the first year after starting available for analysis. The primary outcomes were changes in sRV global longitudinal strain (GLS) and fractional area change (FAC). Longitudinal changes were evaluated using linear mixed models.

Results: Thirty-nine sRV failure patients (46±9.3 years old, 41% female) were included. Twenty-five (64%) had transposition of the great arteries after an atrial switch procedure and 14 (36%) had congenitally corrected transposition. sRV GLS improved significantly in the first 50 days (-1.4%-point per month, p<0.001) and stabilised afterwards (<0.1%-point per month, p=0.520). Though age had a significant overall negative effect on sRV GLS (0.1%-point per year of age, p=0.049), it did not influence the longitudinal changes after starting SGLT2i. sRV FAC also improved in the first 50 days (3.2%-point per month, p=0.002), after which sRV FAC deteriorated in patients with subpulmonary left ventricular pacing (-0.9%-point per month, p=0.012) while it stabilised in patients without pacing (0.1%-point per month, p=0.573). In the first 50 days, tricuspid annular plane systolic excursion also improved significantly in all patients (1.2 mm per month, p=0.006), and stabilised afterwards (p=0.721).

Conclusions: SGLT2i therapy is associated with improvements in systolic ventricular function in sRV failure patients. Despite early improvement in sRV FAC, there was a negative longer term correlation with subpulmonary left ventricular pacing, potentially reflecting adverse effects of subpulmonary ventricular pacing on sRV function.

Keywords: Echocardiography; HEART FAILURE; Heart Defects, Congenital; Pharmacology, Clinical.

Figure 1. Changes in sRV GLS and FAC after starting SGLT2i. (A) Predicted longitudinal change in sRV GLS with 95% CIs. There is a significant improvement in the first 50 days after starting SGLT2i (−1.4%-point per month, p<0.001) and subsequent stabilisation (p=0.520). There was a significant negative effect of age (−0.1%-point per year of age, p=0.049), but age did not influence the temporal changes after starting SGLT2i. (B) Predicted longitudinal change in sRV FAC. There is a similar initial improvement in the first 50 days (3.2%-point per month, p=0.002), followed by a significant deterioration in patients with single-site spLV pacing (−0.9%-point per month, p=0.012). In contrast, patients without spLV pacing remained stable (p=0.573). FAC, fractional area change; FU, follow-up; GLS, global longitudinal strain; SGLT2i, sodium-glucose cotransporter 2 inhibitor; spLV, subpulmonary left ventricle; sRV, systemic right ventricle.

Figure 2. Changes in TAPSE and S’ after starting SGLT2i. (A) Predicted longitudinal change in TAPSE with 95% CIs. A significant improvement can be appreciated in the first 50 days (1.2 mm per month, p=0.006). After 50 days, this was no longer significant (p=0.721). No covariates contributed significantly to the model. (B) Predicted change in S’ over time. Patients with ccTGA had a significant decrease in S’ in the first 50 days (−1.4 cm/s per month, p=0.014), followed by a significant improvement (0.5 cm/s per month, p<0.001). TGA atrial switch patients remained stable. (cc)TGA, (congenitally corrected) transposition of the great arteries; FU, follow-up; SGLT2i, sodium-glucose cotransporter 2 inhibitor; sRV, systemic right ventricle; TAPSE, tricuspid annular plane systolic excursion.

Figure 3. Changes in spLV FWS and FAC after starting SGLT2i. (A) Predicted longitudinal change in spLV FWS (%) with 95% CIs, faceted for sRV anatomical subgroups. There was a significant improvement in the first 50 days for patients without spLV pacing (−1.5%-point per month, p=0.048). This improvement was more pronounced in patients with spLV pacing (−3.9%-point per month, interaction p=0.046). After the first 50 days, there were no significant changes in both groups (p=0.368). Overall, ccTGA patients had a significantly better spLV FWS than TGA atrial switch patients (intercept 6.5%-point, p<0.001). (B) Predicted change in spLV FAC (%) over time. Patients with an escalation in HF pharmacotherapy during follow-up had a significantly higher spLV FAC at baseline (intercept 12.0%-point, p=0.003) and showed a significant deterioration (−2.3%-point per month, p<0.001) compared with patients without an escalation in pharmacotherapy (0.2%-point per month, p=0.237). (cc)TGA, (congenitally corrected) transposition of the great arteries; FAC, fractional area change; FU, follow-up; FWS, free-wall strain; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; spLV, subpulmonary left ventricle; sRV, systemic right ventricle.

Figure 4. Effect of SGLT2i on ventricular function in sRV failure. This real-world evaluation of data from the ACHIEVE-SGLT2i registry demonstrated that SGLT2i are associated with improvements in systolic function in sRV failure patients. sRV GLS improved significantly in the first 50 days and stabilised afterwards. Age at start SGLT2i significantly influenced overall sRV GLS, as indicated by the separate lines for the first quartile (Q1), median and third quartile (Q3) of age. sRV FAC also improved significantly in the first 50 days. After 50 days, patients without spLV pacing remained stable, while patients with spLV pacing deteriorated. (cc)TGA, (congenitally corrected) transposition of the great arteries; FAC, fractional area change; FU, follow-up; GLS, global longitudinal strain; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; spLV, subpulmonary left ventricle; sRV, systemic right ventricle; TTE, transthoracic echocardiography.