impact of vitamin B12 and folate deficiency anemias on cardiorenal outcomes in HFrEF

Background/Introduction Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, despite advances in medical therapy. While iron deficiency anemia is a well-established comorbidity contributing to adverse HF outcomes, the impact of other nutritional anemias, such as vitamin B12 and folate deficiency anemias, on heart failure outcomes remains poorly studied. Purpose This study aims to evaluate the impact of folate or vitamin B12-deficiency anemia on cardiorenal outcomes among patients hospitalized with acute decompensated HFrEF. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (173 health care organizations). ND was defined as low serum folate (<3.0 ng/mL) or low B12 (<200 pg/mL), with a corresponding diagnosis of deficiency anemia. Adults hospitalized with acute or acute-on-chronic HFrEF were stratified into those with documented ND (n=2,292 pre-match) and a reference cohort with normal nutritional status (n=52,668 pre-match). Cohorts were balanced via 1:1 propensity score matching on demographics and AHA PREVENT risk factors. Primary outcomes of recurrent acute decompensated heart failure (ADHF) and secondary outcomes of all-cause mortality, acute kidney injury (AKI), and stroke were assessed over a 5-year follow-up period. Z-tests were performed using relative risk. Risk ratios with 95% CIs were calculated following propensity matching. Results After 1:1 propensity score matching, two well-balanced cohorts of 2,288 patients each were identified (mean age ~65.4 years; 44.7% female; 63.1% White). All-cause mortality did not differ between the two cohorts(11.5% ND vs. 12.6% No ND; RR 0.910, 95% CI 0.778–1.064; p=0.237). There was a higher risk of ADHF recurrence in the ND cohort compared to the reference cohort (28.3% vs. 25.1%; RR 1.127, 95% CI 1.024–1.241; p=0.015). AKI occurrence trended higher in ND patients without reaching significance (27.4% vs. 25.0%; RR 1.094; p=0.069). Stroke rates were low and comparable between groups (3.4% vs. 2.6%; p=0.172). Conclusion(s) In this propensity-matched real-world cohort of patients with acute decompensated HFrEF, concurrent folate or vitamin B12 nutritional anemia was associated with a significantly higher risk of ADHF recurrence but not all-cause mortality. These findings highlight the potential impact of non-iron nutritional deficiencies on cardiorenal outcomes in HFrEF and underscore the need for further prospective studies to clarify their prognostic impact.