Investigation of lactate dehydrogenase isoenzymes as candidate biomarkers of idiopathic pulmonary arterial hypertension

Elizabeth Paratz & Vahitha Abdul-Salam


Elizabeth D Paratz
Sixth Year Medicine (Undergraduate)
Melbourne University

Dr. Vahitha Abdul-Salam
Post-Doctoral Fellow
Imperial College, London

For her final year of Medicine, Elizabeth is based at St Vincent’s Hospital, Melbourne. This research is the work which led to her Bachelor of Medical Science (2007-8), from a year spent based in London at the Hammersmith Hospital (Imperial College).


Abstract

This study investigates the activity and expression of lactate dehydrogenase (LDH) in idiopathic pulmonary arterial hypertension (IPAH) patients. IPAH is a rare and highly fatal disease with a median life expectancy at diagnosis of only 2.8 years. Ideally a simple blood test for biomarkers could simplify the physician’s diagnostic work-up, resulting in earlier diagnosis and successful institution of therapy. Recent publications suggest IPAH may behave like cancer, with monoclonal proliferation and a shared pathway of mitochondrial dysfunction. LDH is often upregulated in cancers, and a similar elevation is suspected in IPAH. Discovering similar patterns of flux in the cellular bioenergetics of IPAH and cancer would support the emerging theory that IPAH has a ‘cancer phenotype’. Quantitative proteomic analysis of fourteen lung tissue homogenate samples (seven lobectomy, seven IPAH) was performed using liquid chromatography – tandem mass spectrometry (LC-MS/MS). The lung samples, as well as 30 plasma samples (ten normal, 20 IPAH) were analysed for LDH fractional isoenzyme activity and expression. A pyruvate-to-lactate spectrophotometric activity assay was performed on the 44 samples, followed by LDH isoenzyme separation on thin-layer agarose gel and densitometric analysis. A significant link exists between IPAH and increased plasma and lung levels of LDH-1 (P = 0.0114 and 0.0262 respectively on Mann-Whitney U test). Receiver Operating Characteristic analysis demonstrated plasma LDH-1 had biomarker sensitivity and specificity of 80%. Measuring plasma LDH-1 appears clinically useful in diagnosing IPAH. This work supports the re-evaluation of IPAH as a cancer-like disease and suggests a new biomarker.