Abstract Body (Do not enter title and authors here):
Background:
Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells that catalyses the forward and backwards conversion of pyruvate to lactate. Tissue LDH concentrations are hundreds of times higher than those in plasma, and cellular damage results in elevated circulating concentrations of LDH. Consequently, increased LDH levels are a non-specific measure of cellular injury in critically ill patients, and are a poor prognostic finding in these individuals. However, whether LDH levels are also prognostically important in heart failure (HF) is unknown.

Hypothesis:
LDH concentration is associated with fatal and non-fatal outcomes in patients with HF and reduced ejection fraction (HFrEF).

Methods:
GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a randomized, double-blind, multicenter, event-driven trial that evaluated the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil (OM) versus placebo in 8,232 patients with HFrEF. The primary outcome was a time-to-first-event analysis of a composite of worsening HF (hospitalization or urgent visit) or cardiovascular death. We assessed associations between baseline LDH and clinical outcomes.

Results:
In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Among outpatients, patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have an ischemic etiology and elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and troponin I. Compared to patients in the lowest LDH quartile Q1 (LDH 155[144-163](U/L)), the hazard ratios (HR) (95% CI) for the primary outcome were Q2 (LDH 183[177-188]): 1.15 (1.02–1.31), Q3 (LDH 207[201-215]): 1.39 (1.23–1.58), and Q4 (LDH 253[236-280]): 1.84 (1.62–2.08), respectively. Even after adjustment for the aforementioned biomarkers and other prognostic variables, elevated LDH remained independently associated with higher HR: Q2 (1.14, 1.00-1.31); Q3 (1.29, 1.13-1.47); and Q4 (1.51, 1.32-1.73). Similar trends were seen for the components of the primary outcome and all-cause mortality (Figure). The treatment effect of OM compared with placebo on clinical outcomes was not modified by LDH subgroups.

Conclusions:
In GALACTIC-HF, higher LDH levels were independently associated with increased risk of fatal and non-fatal outcomes in patients with HFrEF.