Does Sacubitril-Valsartan Improve Myocardial Sympathetic Nervous Activity? An Analysis of the Reverse Remodeling Effects of Entresto (REMODEL) Study.

BackgroundIn chronic heart failure (HF) with reduced ejection fraction (HFrEF), diminished cardiac output triggers neurohormonal activation that worsens cardiac dysfunction.Sacubitril-valsartan improves morbidity and mortality in HFrEF, potentially by modulating sympathetic nervous system activity. ObjectivesTo evaluate the effects of sacubitril-valsartan on myocardial sympathetic innervation using 123meta-iodobenzylguanidine (MIBG) scintigraphy in patients with stable chronic HFrEF. MethodsThe REMODEL study is a prospective, single-arm study including patients with NYHA Class II-IV symptoms and LVEF 25-40%.Participants underwent 123-meta-iodobenzylguanidine (MIBG) scintigraphy a noninvasive measure of myocardial sympathetic innervation assessed by the heart-to-mediastinum (H/M) uptake ratio and washout rate (WR), along with echocardiography, cardiopulmonary testing, biomarker analysis, and quality of life assessment at baseline, 3, 6, and 12 months after initiating sacubitril-valsartan. Sacubitril-valsartan was initiated at 24/26 mg or 49/51 mg twice daily and uptitrated to 97/103 mg twice daily over approximately 2 weeks.The primary endpoint was change in late H/M ratio from baseline to 3 months, assessed using the Wilcoxon signed-rank test and Spearman rank correlations. ResultsAmong 40 enrolled patients, 39 completed baseline and 3-month MIBG imaging; 26 completed 12-month follow-up.At 3 months, MIBG parameters improved: late H/M ratio increased from 1.39 0.19 to 1.52 0.19 (p<0.001) and washout rate declined from 48.1 13.8% to 32.1 7.8% (p<0.001).Biomarker: NT-proBNP decreased from 333 to 210 [79-760] pg/mL (p<0.001).Functional: 6MWT improved (431 [341-500] to 442 [359-522] m, p=0.006); peak VO increased nonsignificantly (17.6 to 18.7 mL/kg/min, p=0.11).Change in washout rate was statistically correlated with NT-proBNP change (Spearman's rho = 0.44, p = 0.005), but not with functional measures.At 12 months, VO improved to 19.8 mL/kg/min (p=0.019) and 6MWT increased by 56.4 m (p<0.001), while NT-proBNP decline was nonsignificant. ConclusionsIn this single-arm study, sacubitril-valsartan was associated with improved myocardial sympathetic activity in HFrEF patients.Changes in washout rate were statistically correlated with improvements in NT-proBNP (Spearman rho=0.44,p=0.005), and changes in late H/M ratio were statistically correlated with reduction in LVEDD (rho= -0.35, p=0.030).However, these changes did not correlate with functional measures.In the absence of a control arm, causal attribution to sacubitril-valsartan cannot be established.These findings suggest the need for further investigation into the prognostic relevance of MIBG-derived sympathetic activity markers.