Biomarkers for the Early Stages of Heart Failure

The Challenge: Understanding the Early Stages of Heart Failure

Cardiovascular disease (CVD) continues to be the leading cause of death worldwide, despite significant advances in the treatment of CVD. A major contributor to these deaths is high blood pressure (hypertension). Chronic hypertension leads to left ventricular hypertrophy (LVH) and, eventually, heart failure (HF). HF has been linked to high morbidity and mortality rates, with 1-year mortality rates as high as 22%. Early detection and prevention of LVH are thus essential; however, more mechanistic studies are needed to understand the early stages of HF. The spontaneously hypertensive rat (SHR) is the most studied animal model of hypertension and is used to study cardiovascular disease progression. SHRs are widely used to examine the transition from LVH to HF because their slow progression to HF mimics human disease. LVH and HF have been linked to metabolic abnormalities. Metabolomics offers a unique opportunity to identify perturbations in heart metabolism before and during the development of LVH and to create treatment strategies to prevent LVH.

Metabolon Insight: Unraveling Metabolic Mechanisms Related to Heart Failure

This study utilized the Metabolon Global Discovery Panel to profile the hearts of SHRs and control rats.¹ The goal was to compare the metabolomic profiles of SHRs during early hypertension development to control rats. The Global Discovery Panel has unrivaled coverage of over 5,400 semi-quantifiable analytes and offered this research group the most comprehensive solution for comparing the metabolomic profiles of SHRs during early hypertension development to control rats.  This provided a foundation of knowledge for elucidating common traits and relationships between SHR cohorts compared to their control group.

The Solution: Metabolomics Assesses Metabolic Changes Associated with Hypertension Development

To assess metabolic changes in SHR hearts, the research team performed an untargeted metabolomic analysis of SHR and control hearts at two months of age. Data analysis revealed significant differences in several energy-providing metabolic pathways, such as fatty acid, glucose, and branched-chain amino acid (BCAA) metabolism. Most remarkably, fatty acyl-carnitines, all BCAAs (leucine, isoleucine, and valine), BCAA-derived carnitines, and a few long-chain free fatty acids were increased. Increased levels of lactate and pyruvate and decreased dihydroxyacetone phosphate levels reflected changes in glucose metabolism. Metabolites within the glycogen breakdown pathway were significantly reduced, while aldose reductase/polyol pathway products increased. Several nucleotide metabolites, such as purine and pyrimidine, were significantly decreased in SHR hearts, but others, such as adenosine monophosphate (AMP), adenosine diphosphate (ADP), and dihydroorotate were elevated.

Oxidative stress in SHR hearts was determined via substantial increases in lipid oxidation and peroxidation products (monohydroxy fatty acids, fatty acid dicarboxylates, oxidized fatty acid 4-hydroxy-2-noneal, eicosanoids, 7-hydroxycholesterol, and endocannabinoids). Three amino acids necessary for glutathione synthesis were decreased. Other remarkable lipid abnormalities in SHR hearts were changes in diacylglycerols, membrane phospholipids, sphingolipids, and ceramide levels.

The Outcome: Novel Biomarkers for the Early Detection of Heart Failure

This study provides a comprehensive metabolite analysis of SHR hearts, offering insights into the changes in cardiac energy metabolism early in hypertension development. The early detection of metabolic abnormalities related to hypertension-induced LVH could allow for earlier detection and treatment of this medical condition and may offer a novel approach to preventing HF in patients with hypertension-induced LVH.