Christina Kronberger, Oliver Domenig, Noémi Pávó, Johannes J. Kovarik, Franz Duca, René Rettl, Michael Poledniczek, Lena Marie Schmid, Nikita Ermolaev, Mahshid Eslami, Luciana Camuz Ligios, Christian Hengstenberg, Roza Badr Eslam, Jutta Bergler-Klein, Johannes Kästner, Andreas A. Kammerlander, Christina Binder
AIM: This study aimed to characterize circulating renin-angiotensin-aldosterone system (RAAS) patterns in transthyretin amyloid cardiomyopathy (ATTR-CM), examine their relationship with clinical and echocardiographic parameters and determine their prognostic value. METHODS: In this prospective study, ATTR-CM patients underwent serum quantification of classical (angiotensin I-IV, aldosterone) and alternative (angiotensin 1-7, angiotensin 1-5) RAAS peptides and angiotensin converting enzyme 2 (ACE2) activity using mass spectrometry. RAAS inhibitor use was recorded. Associations of RAAS peptides with N-terminal pro brain natriuretic peptide (NT-proBNP) and echocardiographic parameters were analyzed. Prognostic associations with the composite endpoint of HF hospitalization or cardiac death were assessed using Kaplan-Meier curves stratified by median peptide values. RESULTS: Among 137 patients, RAAS inhibitor use included ACEi (21.2%), ARBs (34.3%), ARNIs (7.3%) and none (26.0%). RAAS profiles were consistent with the expected effects of the respective RAAS inhibitors. During a median follow-up of 1.6 years, 49 patients (36%) experienced the composite endpoint. Patients with adverse cardiac events had higher ACE2 activity (p<0.001) and alternative RAAS peptides (angiotensin 1-7: p=0.007; angiotensin 1-5: p<0.001). Higher ACE2 activity was associated with higher NT-proBNP (p<0.001) and more advanced echocardiographic markers of biventricular dysfunction. In Kaplan Meier analysis, ACE2 above median predicted adverse cardiac outcomes (p=0.017), while classical RAAS peptides were not predictive. CONCLUSION: ATTR-CM patients exhibit distinct RAAS profiles, with increased ACE2 activity and a shift toward the alternative RAAS axis in more advanced disease. Higher ACE2 activity is associated with higher NT-proBNP, biventricular dysfunction and adverse cardiac outcomes, suggesting that ACE2 may represent a promising marker for risk stratification in ATTR-CM.