The classical- and alternative renin-angiotensin-aldosterone-system (RAAS) in HFpEF and cardiac amyloidosis - a cohort comparison of angiotensin profiles

Background and aim The Renin-Angiotensin-Aldosterone-System (RAAS) plays a central role in heart failure (HF) pathophysiology. While the classical RAAS-pathway (cRAAS) has been extensively studied, less is known about the alternative RAAS-pathway (aRAAS), which exerts vasodilatory and antifibrotic effects. Both pathways are shown in Figure 1. Cardiac amyloidosis (CA) and HF with preserved ejection fraction (HFpEF) share key pathophysiological features, including diastolic dysfunction and myocardial fibrosis; however, RAAS inhibitor (RAASi) has not consistently demonstrated improved clinical outcomes in either population. A deeper understanding of RAAS signaling in these specific disease entities is therefore needed. We aimed to compare cRAAS and aRAAS profiles in patients with CA and HFpEF Methods In this observational study, participants with wild-type CA and HFpEF were prospectively included between 22.12.2010 and 18.02.2025. Serum samples were obtained at baseline (time of diagnosis), and angiotensin concentrations were measured using tandem mass spectrometry. Additionally, surrogate markers were calculated: PRA-S; sum of angiotensin I and angiotensin II), ACE-S (angiotensin II/angiotensin I ratio), and AA2 ratio (aldosterone/angiotensin II). RAAS components were compared between groups and stratified according to treatment with RAAS inhibitors (RAASi). Group differences were assessed using non-parametric tests with post-hoc pairwise comparisons. Results Our study included a total of 287 patients (CA n= 137; HFpEF n=150). Compared with HFpEF, patients with CA showed higher levels of angiotensin 1-7 (7.3 [3.0-21.8] vs. 3.4 [2.5-15.4], p <0.001), indicating enhanced aRAAS activity. ACE-S was also higher in CA (3.0 [1.8-3.6] vs. 1.5 [0.3-2.1], p<0.001), whereas angiotensin I was higher in HFpEF (188.5 [52.2-654.8] vs 115.5 [36.2-277.1], p=0.012). Components of the cRAAS, including angiotensin II, aldosterone, PRA-S and AA2 ratio, did not differ significantly between groups (Table 1). In the HFpEF cohort, 114 patients (76%) received RAASi, whereas 76 patients (55.5%) in the CA cohort were treated with RAASi. RAASi was associated with higher angiotensin I and angiotensin 1-7 levels and lower ACE activity in both groups. Importantly, pairwise comparisons confirmed significantly higher angiotensin 1-7 and ACE-S concentrations in CA compared with HFpEF, irrespective of RAASi use. Conclusion We were able to show that CA is associated with a distinct RAAS profile characterized by increased activity of the aRAAS pathway, reflected by higher angiotensin 1-7 levels, compared with HFpEF. This difference persists despite RAASi therapy, suggesting disease-specific RAAS changes beyond pharmacological effects.Classical vs. Alternative RAAS PathwaysRAAS Profiles: HFpEF vs.