The Promise of Omics for Detecting and Treating Cardiometabolic Risk

Recent global increases in cardiometabolic risk (CMR) factors and their long-term consequences on cardiovascular disease and mortality are the biggest current challenges in cardiovascular prevention and may have significant negative impact on cardiovascular mortality rates, as noted in the recent blunting in the decline of cardiovascular mortality. The majority (70-80%) of US children and adults have suboptimal or poor cardiovascular health which declines with age beginning from ages 2 to 5 years and is driven by lifestyle including unhealthful diet, physical inactivity, and overweight/obesity. ¹ The decline in age-adjusted cardiovascular disease burden that has been seen over the past several decades may be ending, and new global preventive measures will be required to change this trajectory.²

CMR and related diseases are not only increasing in prevalence but also increase socioeconomic disparities. CMR starts early yet is identified late. In order to address the root causes of cardiometabolic diseases and their prevention early in life, this AHA statement³ on "Next Generation, Modifiable Cardiometabolic Biomarkers" discusses several emerging biomarkers of CMR (early, mechanistic, and modifiable) across 5 omics technologies (epigenome, microbiome, metabolome, lipidome, inflammasome) that may detect the early transition from cardiometabolic health to metabolic dysregulation.

CMR diseases are increasingly recognized as disorders of metabolic inflexibility in which energy surplus due to excess nutrition and physical inactivity result in energy dysregulation and impaired fuel switching at the mitochondrial level. The key clinical features of ectopic visceral (central) adiposity and insulin resistance are identified late; hence, the focus of this statement is on the earlier abnormalities that alter mitochondrial function and energetics. Metabolic health deteriorates as the mitochondria – the respiratory engine of the cell - lose their resilience, i.e. the ability to switch freely between energy substrates (e.g., fats and sugars)⁴.

The AHA statement summarizes the three key features (early, mechanistic, and modifiable) of an optimal biomarker: 1) Early and precise clinical detection before the current thresholds for pathophysiology are crossed; 2) Mechanistic targets of intervention (i.e., within causal pathways); and 3) Modifiable.

Recent advances in omics technologies have led to better understanding of CMR disease mechanisms. This AHA statement addresses an important and emerging area of biomedical science involving 5 omic technologies that can detect CMR early in life and throughout the lifespan, highlighting novel omic biomarkers that are early, mechanistic, and modifiable. The statement additionally offers a research agenda and opportunities for identifying both omic biomarkers and lifestyle approaches to promote early and personalized CMR prevention.

The 5 omic systems that are discussed in the context of CMR include:

1. Epigenomics: The heritable changes in gene expression that are not coded in somatic or mitochondrial DNA; in addition, the epigenome modulates gene expression in response to the environment. Epigenomics includes DNA methylation (somatic and mitochondrial), noncoding RNA, and posttranslational histone modifications. For example, exposure to childhood adversity has been associated with changes in DNA methylation and gene expression. Studies have also shown associations between epigenetic markers, CMR, and premature cardiovascular disease in youth and adults. Ambient air pollution, in particular during pregnancy, has been associated with abnormalities in mitochondrial DNA methylation. Promising therapeutic interventions involve "epidrugs", chemical compounds that specifically target epigenetic marks to reverse deleterious epigenetic changes. Further, lifestyle interventions that attenuate CMR have been related to favorable DNA methylation reprogramming.
2. Gut Microbiome: The trillions of gut bacteria and microorganisms and their genetic material comprise the gut microbiome. Gut microbiome disturbances are associated with CMR including obesity, hypertension, diabetes, dyslipidemia and cardiovascular diseases. The diversity and functional capacity of the gut microbiome is established early in life, possibly in utero, and may have lasting effects on CMR and cardiovascular disease throughout life. Mechanisms include interactions with the immune system, metabolism (e.g., short chain fatty acids such as butyrate which is produced by fermentation of dietary fiber), inflammation, and microbial translocation. The gut microbiome is modified particularly by diet but also other lifestyle factors (e.g., physical activity, sleep, psychosocial stress, environmental microbial exposures, drugs in particular antibiotics, and infections.)
3. Metabolome: Thousands of small low-molecular weight molecules that reflect genetic, epigenetic, transcriptomic, and proteomic interactions with the environment, including with the gut microbiome. Metabolomics has been used clinically for detecting inborn errors of metabolism in newborns. The metabolome is very dynamic across the lifespan as it reflects continuous interaction between numerous biological and metabolic processes with the environment. Metabolites are altered by lifestyle (diet, exercise, weight loss) and pharmacologic interventions. For example, branched chain amino acids (valine, leucine and isoleucine) are essential amino acids that are metabolites of protein catabolism which have been causally associated with CMR (insulin resistance and diabetes) and can be modified by changes in diet, activity, and surgical weight loss.
4. Lipidome: Lipids are a subset of the metabolome. Lipids are important components of all cell membranes, in addition to serving important functions in cellular regulation, signaling, energy storage and ectopic lipotoxicity. Lipid metabolism is key to CMR beyond the standard lipids (e.g., triglycerides and cholesterol). For example, excess ceramides impair mitochondrial function and have been linked to pregnancy related conditions (gestational diabetes, preeclampsia, and eclampsia), nonalcoholic fatty liver disease/steatohepatitis, ectopic adiposity, insulin resistance, diabetes and cardiovascular disease. The lipidome is highly modifiable with diet, with a strong favorable link to the plant-based Mediterranean diet and dietary omega 3 fatty acids, and unfavorable effects of high saturated fat diets. This underscores the importance of a healthful diet early in life to ensure functional lipid metabolism, a healthy life trajectory and reduced CMR and related diseases.
5. Inflammasome: Inflammation is a normal function of the innate immune response necessary for maintaining homeostasis in response to local or systemic stress or injury. Inflammasomes are large intracellular multiprotein complexes that fight injury and infection through inflammation. However, aberrant inflammasome activation can lead to the uncontrolled tissue responses that underlie various diseases including CMR, cardiovascular disease, autoimmune (e.g. inflammatory bowel disease, rheumatologic diseases) and neurogenerative disorders, and cancer. The relationship between inflammation and CMR can be bidirectional and reinforcing. The NLRP3 inflammasome is the most relevant to CMR and has been mechanistically linked to insulin resistance, ectopic obesity, cardiovascular diseases, and several other inflammatory diseases. The Mediterranean diet and physical activity are important anti-inflammatory lifestyle interventions that can be initiated early and have lifelong benefits.

In summary, this AHA statement focuses on emerging omic biomarkers that can detect CMR throughout the lifespan, highlighting novel biomarkers that are early, mechanistic, and modifiable. It draws attention to the central role of mitochondrial flexibility which can become inflexible under conditions of nutrient excess resulting in impaired energetics and dysregulated metabolism, the underlying drivers of CMR. At the same time, this provides opportunities for therapeutic and lifestyle interventions, particularly relating to diet and exercise, which can promote metabolic flexibility, improve metabolic health, and reverse CMR, in particular when initiated early in life and sustained throughout the lifespan.