Mechanisms and Prognosis of Intolerance to Angiotensin Receptor-Neprilysin Inhibitors in Advanced Heart Failure: Insights From Vasodilator Challenge

Giulio Cacioli; Guglielmo Gallone; Alessandro Verde; Michele Ciabatti; Stefano Pidello; Valentina Colombo; Ludovica De Fazio; Vanessa Peano; Giacomo Angeli; Federica De Donno; Pier Paolo Bocchino; Luciana D'Angelo; Piero Gentile; Fabrizio D'Ascenzo; Paola Lilla Della Monica; Vito Piazza; Federico Conrotto; Gabriella Masciocco; Claudia Raineri; Fabio Sbaraglia; Giampaolo Luzi; Andrea Garascia; Federico Ranocchi; Ryan J Tedford; Gaetano Maria De Ferrari

doi:10.1016/j.cjca.2025.02.019

Mechanisms and Prognosis of Intolerance to Angiotensin Receptor-Neprilysin Inhibitors in Advanced Heart Failure: Insights From Vasodilator Challenge

Can J Cardiol. 2025 Feb 14:S0828-282X(25)00129-1. doi: 10.1016/j.cjca.2025.02.019. Online ahead of print.

Authors

Giulio Cacioli¹, Guglielmo Gallone², Alessandro Verde³, Michele Ciabatti⁴, Stefano Pidello², Valentina Colombo³, Ludovica De Fazio⁵, Vanessa Peano², Giacomo Angeli⁶, Federica De Donno³, Pier Paolo Bocchino⁷, Luciana D'Angelo³, Piero Gentile³, Fabrizio D'Ascenzo⁷, Paola Lilla Della Monica⁵, Vito Piazza⁵, Federico Conrotto⁷, Gabriella Masciocco³, Claudia Raineri², Fabio Sbaraglia⁵, Giampaolo Luzi⁵, Andrea Garascia³, Federico Ranocchi⁵, Ryan J Tedford⁸, Gaetano Maria De Ferrari²

Affiliations

¹ Cardiac Surgery and Heart Transplant Unit, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy. Electronic address: giulio.cacioli@gmail.com.
² Division of Cardiology, Cardiovascular and Thoracic Department, "Città della Salute e della Scienza" Hospital, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy.
³ "De Gasperis" Cardio Center, Niguarda Hospital, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
⁴ Cardiac Surgery and Heart Transplant Unit, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy; Cardiovascular Department, San Donato Hospital, Arezzo, Italy.
⁵ Cardiac Surgery and Heart Transplant Unit, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.
⁶ Department of Medical Sciences, University of Turin, Turin, Italy.
⁷ Division of Cardiology, Cardiovascular and Thoracic Department, "Città della Salute e della Scienza" Hospital, Turin, Italy.
⁸ Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

PMID: 39956377
DOI: 10.1016/j.cjca.2025.02.019

Abstract

Background: Angiotensin receptor-neprilysin inhibitor (ARNI) intolerance is common in patients with advanced heart failure (AdHF) and may be associated with worse prognosis. During right heart catheterization (RHC), afterload reduction induced by vasodilator challenge may reproduce the hemodynamic effects of ARNI. Through sodium nitroprusside (NTP) infusion, we characterized the hemodynamic mechanisms of ARNI intolerance and explored its prognostic relevance in AdHF.

Methods: We performed a retrospective, multicenter study evaluating AdHF patients undergoing RHC with NTP infusion. Hemodynamic ARNI intolerance was defined as symptomatic hypotension requiring ARNI cessation. We collected clinical, echocardiographic, and hemodynamic parameters at baseline and after vasodilator challenge and evaluated their association with ARNI intolerance and a composite clinical outcome of 1-year all-cause death, urgent heart transplantation, or LVAD implantation.

Results: Of the 116 consecutive patients, hemodynamic ARNI intolerance was seen in 26 (22.4%). Baseline hemodynamics were not associated with ARNI intolerance. After NTP infusion, a smaller increase in stroke volume index (ΔSVi; adjusted odds ratio [adj-OR] per mL increase: 0.89, 95% confidence interval [CI] 0.81-0.99, P = 0.031) and higher pulmonary elastance (post-NTP arterial elastance; adj-OR per mm Hg per mL increase: 6.49, 95% confidence interval [CI] 1.04-40.46, P = 0.045) were independently associated with hemodynamic ARNI intolerance. Patients with ARNI intolerance were more likely to experience the primary outcome (Kaplan-Meier estimates: 73.0% vs 36.2%, P = 0.021). Higher baseline right atrial pressure/pulmonary artery wedge pressure (hazard ratio [HR] 8.57, 95% CI 2.23-32.89, P = 0.002) and lower post-NTP SVi (HR 0.95, 95% CI 0.92-0.99, P = 0.015) were independent predictors of adverse events.

Conclusions: Among AdHF patients, ARNI intolerance is common and associated with worse outcomes. NTP infusion unveils exhausted hemodynamic reserve as its underlying mechanism and prognostic determinant.