OBJECTIVE To evaluate the clinical efficacy of Zhuling Decoction combined with standard therapy in patients with heart failure (HF) complicated by diuretic resistance (DR) and presenting with the traditional Chinese medicine (TCM) syndrome of qi-yin deficiency, blood stasis, and fluid retention, and to explore its effects on the arginine vasopressin (AVP)-protein kinase A (PKA)-aquaporin-2 (AQP2)-related water reabsorption pathway.

METHODS This study was a randomized controlled trial with an open-label design and blinded outcome assessment. Eighty hospitalized patients with HF complicated by DR and diagnosed with qi-yin deficiency, blood stasis, and fluid retention syndrome were enrolled from Taicang Hospital of Nanjing University of Chinese Medicine between September 2023 and February 2026 and randomly assigned to an intervention group or a control group, with 40 patients in each group. The control group received a standardized Western medicine regimen comprising standard anti-HF therapy and intensive diuretic treatment, while the observation group received Zhuling Decoction in addition to the control group's regimen; both groups were treated for two consecutive weeks. Before treatment and after two weeks of treatment, the following parameters were assessed: 24-h urine volume; serum N-terminal pro-B-type natriuretic peptide (NT-proBNP); indicators related to the AVP-PKA-AQP2 pathway urinary AQP2, AVP, cyclic adenosine monophosphate (cAMP), PKA, arginine vasopressin V2 receptor (AVPR2), and adenylate cyclases (ADCY3, ADCY6, ADCY9); indicators related to the renin-angiotensin-aldosterone system (RAAS); TCM syndrome scores; and TCM clinical efficacy. Quality of life was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) before treatment and 30 days after enrollment.

RESULTS After 2 weeks of treatment, 24-h urine volume increased significantly in both groups compared with baseline, and was significantly higher in the intervention group than in the control group (P0.01). NT-proBNP levels decreased significantly in both groups, with a greater reduction in the intervention group than in the control group (P0.05). After treatment, urinary AQP2 and serum levels of AVP, cAMP, PKA, AVPR2, ADCY3, ADCY6, and ADCY9 were all lower in the intervention group than in the control group (P0.05, P0.01). No significant between-group differences were observed in RAAS-related indices (P0.05). Total TCM syndrome scores decreased significantly in both groups, with lower post-treatment scores in the intervention group than in the control group (P0.01). The overall response rate was 92.5% in the intervention group, significantly higher than 75.0% in the control group (P0.05). No serious adverse events occurred during treatment. At 30 days after enrollment, two patients in the intervention group and three in the control group were lost to follow-up. MLHFQ scores decreased significantly in both groups, and were significantly lower in the intervention group than in the control group (P0.01).

CONCLUSION On the basis of standard therapy, Zhuling Decoction further improved short-term diuretic response, reduced NT-proBNP levels, and enhanced quality of life in patients with HF complicated by DR and characterized by qi-yin deficiency, blood stasis, and fluid retention syndrome. Its therapeutic effects may be associated with modulation of the AVP-PKA-AQP2-related water reabsorption pathway and inhibition of collecting duct water reabsorption.