Metabolomics and Cardiovascular Disease

With the development of social economy, people's lifestyles are constantly changing. Currently, the prevalence and mortality of cardiovascular diseases (CVD) are increasing year by year. About 92.1 million people in the United States suffer from CVD, including 16 million coronary heart disease (CHD) patients, and 1 in 7 people die from CHD. Effective measures to curb the rising prevalence and mortality of CVD have become a major goal of research efforts. With the continuous development of high-throughput and high-sensitivity technologies such as mass spectrometry, metabolomics technologies are increasingly used in CVD research.

Metabolomics Strategies

Untargeted metabolomics is a comprehensive analytical technique that attempts to detect, identify, and relatively quantify as many metabolites as possible from biological samples with the aim of distinguishing unique metabolite profiles associated with specific genotypes, pharmacological treatments, and clinical subgroups. The most significant challenge facing this technology is metabolite identification.

Unlike untargeted metabolomics, targeted metabolomics supports custom analysis of a selected set of metabolites, leading to absolute quantification. The advantages offered by targeted technologies are higher sensitivity and selectivity.

Fig 1. General metabolomics workflow (McGarrah et al., 2018).

Metabolomics in Cardiovascular Disease

Metabolomics and CHD

The diagnosis of CHD is important for the treatment and prognosis of patients. Coronary angiography remains the "gold standard" for visualizing and accurately assessing the extent of coronary artery disease, but coronary angiography is an invasive test. The search for simple and non-invasive biomarkers for the diagnosis, evaluation and adjunctive treatment of CHD has become a hot topic of research. A comprehensive metabolomic profile can help to investigate the pathogenesis of CHD. The discovery of new metabolic markers may assist in the early diagnosis, prognostic assessment and personalized treatment of CHD, and the identification of metabolic markers and their regulatory enzymes may lead to the identification of candidate targets and pharmacological intervention mechanisms for the treatment of CHD.

Metabolomics and myocardial infarction

Myocardial infarction (MI) is a clinically common and severe type of CHD with rapid onset and high lethality. How to diagnose MI early becomes the key to save patients' lives. MI injury triggers changes in gene transcription, protein expression and metabolite concentrations, which are the biological features of cardiac dysfunction. Detection of these biochemical changes has revealed biomarkers such as creatine kinase, creatine kinase isoenzyme, cardiac troponin I and troponin T. However, the sensitivity (35% for both creatine kinase isoenzyme and cardiac troponin I) and specificity (85% and 86% for creatine kinase isoenzyme and cardiac troponin I, respectively) of these biomarkers are low, and they can only be detected at least 4 to 6 h after myocardial injury. These myocardial injury markers could only be detected at least 4~6 h after myocardial injury.

In recent years, due to advances in science and technology and testing tools, high-sensitivity troponins have significantly reduced the time to diagnosis. The presence of each of these biomarkers represents that the cardiomyocyte is in an irreversible state. In contrast, metabolomics studies have shown that metabolite changes are evident as early as 10 min of myocardial injury. And one study found a sensitivity of 94.5% and a specificity of 95.3% for serum differential metabolite changes in patients with MI compared with patients with unstable angina. Changes in metabolic profiles and disturbed metabolic pathways also provide a more comprehensive understanding of the pathophysiological mechanisms of MI. Exploring the metabolite profile provides new insights into the metabolic processes involved in acute MI, and these changes will facilitate timely and rapid clinical assessment of MI in emergency situations, providing more favorable conditions for early diagnosis and treatment of MI, as well as reducing the mortality of MI.

Metabolomics and heart failure

Heart failure is a complex syndrome that is the end stage of all heart diseases. Alterations in cardiac metabolism can be detected in the body fluids of patients. It has been shown that plasma metabolic profiles have significant diagnostic and prognostic value in patients with ischemic heart failure alone or in combination with brain natriuretic peptides.

Alterations in energy utilization and cellular metabolism of the heart have been major issues in heart failure research. Under normal metabolic conditions, fatty acids are the main source of energy for the myocardium, and β-oxidation generates 50% to 70% of myocardial energy consumption of ATP. In contrast, in failing myocardium, the main energy source of the myocardium shifts from the use of fatty acids to glucose and ketone bodies. The use of metabolomics technologies has the opportunity to identify metabolic biomarkers in failing myocardial cells and to identify new molecular mechanisms that may lead to the discovery of new therapeutic approaches that can contribute to the early detection of heart failure, targeted drug therapy, and improved prognosis.

Reference

1. McGarrah, R. W., Crown, S. B., Zhang, G. F., Shah, S. H., & Newgard, C. B. (2018). Cardiovascular metabolomics. Circulation research, 122(9), 1238-1258.