Prognostic impact of cardio-renal-metabolic syndrome in HFrEF from an emerging economy
A Perez Perez, G Gil Garduno, G Medina Avalos, C Martinez Medrano, V Gomez Johnson, S Lopez Gil, A Alvarez Sangabriel, J De La Fuente Mancera, C Guizar Sanchez, L Torres-Araujo, M Aguilar Serrano, E Berrios Barcenas, F Baranda Tovar, A Jordan RiosAbstract
Background
Patients with heart failure (HF) frequently present with overlapping cardiometabolic and renal comorbidities, conferring increased vulnerability to adverse clinical outcomes. The cardio–kidney–metabolic (CKM) framework has emerged as an integrative model to identify high-risk phenotypes; however, its prognostic significance in HF populations remains incompletely characterised.
Purpose
To evaluate the prognostic implications of a high-risk CKM phenotype in a cohort of patients with heart failure with reduced ejection fraction (HFrEF).
Methods
We analysed data from a prospective cohort of 1,000 consecutive patients with established HFrEF initiating chronic outpatient follow-up at a specialised heart failure clinic between 2023 and 2025 in Mexico City. Patients were categorised into two groups: CKM1 (LVEF <40%, estimated glomerular filtration rate <60 mL/min/1.73 m², and type 2 diabetes mellitus) and CKM2 (absence of these criteria). Baseline demographic and clinical variables were collected. The primary outcome was the occurrence of a first unplanned emergency department (ED) visit due to HFrEF decompensation. Multivariable robust Poisson regression, Kaplan–Meier survival analysis, and log-rank testing were performed.
Results
The cohort was predominantly male (70%); 45% had type 2 diabetes and 51% hypertension. Median eGFR was 72.5 mL/min/1.73 m² (IQR 52.4–90.5), mean ejection fraction was 30.3% (SD 11.8), median LDL cholesterol was 79.1 mg/dL (IQR 58–107), and median HbA1c was 6.2% (IQR 5.8–7.0). In multivariable analysis adjusted for age, sex, hypertension, dyslipidaemia, prior ischaemic heart disease, body mass index, and KCCQ score, the CKM1 phenotype was independently associated with a higher risk of unplanned ED visits compared with CKM2 (adjusted RR 1.41; 95% CI 1.21–1.64; p<0.001; N=506). Time-to-first ED visit endopint was significantly shorter in CKM1 phenotype throughout follow-up (log-rank p<0.0001).
Conclusion
In this prospective real-world cohort of patients with HFrEF, the presence of a high-risk cardio–renal–metabolic phenotype was independently associated with an increased risk of clinical decompensation, manifested as unplanned emergency department visits. The early and sustained divergence of cumulative incidence curves underscores the prognostic value of the CKM syndrome beyond traditional risk factors. These findings, derived from routine clinical practice in an emerging economy, highlight the need for targeted risk stratification and integrated management strategies in this particularly vulnerable HFrEF subgroup.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.