Response to letter regarding the article ‘Clinical profiles and prognostic impact of residual intravascular and tissue congestion in acute heart failure’

We sincerely thank Qi et al.1 for their interest in our recent publication on residual congestion phenotypes in patients with acute heart failure (AHF) and we appreciate the opportunity to address the points raised in their correspondence. First, the authors appropriately highlight that the clinical assessment of congestion overall suffers from inter-observer variability and limited sensitivity and specificity, particularly for pulmonary rales and peripheral oedema.2 Despite their limitations, these clinical markers still distinguished different congestion phenotypes, supporting that they reflect meaningful and distinct clinical states. Furthermore, as discussed in the main manuscript, random misclassification between phenotypes would bias the results towards the null hypothesis, suggesting that more objective phenotyping may reveal even stronger differences. Building on this, we agree that more accurate phenotyping may be achieved by using imaging modalities such as lung/cardiac ultrasound and X-rays, as well as invasive pressure measurements. Further, biomarkers offer an additional easy-to-use, objective way to measure congestion.3 Indeed, in our study we showed that biologically active adrenomedullin (bio-ADM) and carbohydrate antigen 125 (CA-125) concentrations are elevated in those with residual congestion. However, it is still unclear if these biomarkers could differentiate between congestion phenotypes. We are currently conducting the prospective PROFILE-AHF study (NCT06587854), which includes repeated extensive multi-modal phenotyping (lung, renal, cardiac ultrasound, and liver elastography) and a mechanistic sub-study to identify biomarkers of peripheral venous congestion. With this study, we aim to provide further insights on the prevalence of distinct congestion phenotypes and study their association with response to therapy and outcomes in contemporary AHF patients. Still, repeated comprehensive imaging is not always feasible in routine clinical settings and our findings illustrate that simple clinical examination, which is fast and inexpensive, remains effective in identifying residual congestion.