AIMS: Inter-atrial shunt device therapy has shown mixed results in clinical trials, with clinical 'non-responders' typically showing features of more advanced heart failure. We aimed to analyse the haemodynamic and clinical response of a novel left atrial to coronary sinus (LA-CS) shunt device in patients with higher natriuretic peptide (NP) levels, a marker of disease severity. METHODS AND RESULTS: An analysis population (n = 95) of patients from the ALT-FLOW early feasibility study with left ventricular ejection fraction >
40% and 1-year follow up was analysed. The cohort was divided into low and high subgroups based on NP levels [b-type natriuretic peptide (BNP) and n-terminal pro BNP (NT-proBNP)]. The mean BNP and NT-proBNP levels for low versus high subgroups were 64.2 ± 34.3 versus 261 ± 103 and 322 ± 269 versus 2050 ± 1070 pg/mL, respectively. Patients in the high NP subgroup had evidence of more advanced disease including worse haemodynamic profiles, lower estimated glomerular filtration rate, and higher percentages of atrial fibrillation. The high NP subgroup experienced significant improvements in KCCQ-OSS and NYHA functional class (P <
0.0001 and P <
0.001, respectively) and to a similar magnitude compared with the low NP subgroup. Compared with pre-implant baseline, workload adjusted pulmonary artery wedge pressure at peak exercise declined in the high NP subgroup (PCWL, 164.1 vs. 96.0 mmHg/W/kg at 6 months, P <
0.003) as well as the low NP subgroup (115.9 vs. 65.9 mmHg/W/keg at 6 months, P <
0.001). Importantly, in both NP subgroups, there was preservation of cardiac index through 6 months as well as right ventricular structure (right ventricular diastolic dimension) and function (tricuspid annular systolic plane excursion) through 1 year. CONCLUSIONS: The quality-of-life, haemodynamic, and functional class improvements along with stable right heart function seen in ALT-FLOW study of LA-CS shunt remain consistent in the subgroup with highest NP levels. This suggests that shunting location could influence outcomes in symptomatic heart failure patients.