Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. Methods and results: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31–73), 150 W (125–175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05–0.11), 0.06 mmol/L/W (0.05–0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03–0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m² (3.7–5.5) in HFpEF, 5.2 L/min/m² (4.3–6.2; P < 0.001) in NCD, and 9.1 L/min/m² (8.0–9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175–1986) vs. 1758 mL/min (1361–2282; P = 0.024) in NCD and 3117 mL/min (2667–3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). Conclusions: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.