Cardiovascular disease (CVD) remains the leading cause of death and morbidity in Western countries, and new therapeutic targets that contribute to the development and progression of CVD are needed.
The study, published in Cell, hypothesized that the use of untargeted metabolomics as a discovery platform, coupled with functional studies, could serve as a relatively unbiased approach to reveal new metabolic pathways in humans that potentially contribute to the development of MCV.
Therefore, they sought to identify circulating metabolites that were increased in non-diabetics as well as in people with type 2 diabetes (an independent risk factor for cardiovascular disease), associated with the development of cardiovascular disease and weakly correlated with glycemic control indices.
The research team was led by Stanley Hazen, MD, Ph.D., chair of the Department of Cardiovascular and Metabolic Sciences at the Lerner Research Institute and Head of the Preventive Cardiology and Rehabilitation Co-section at the Miller Family Heart, Vascular & Thoracic Institute in Cleveland discovered that when phenylalanine is broken down by microbes in the gut, it produces a byproduct (metabolite) that eventually appears in the blood called phenylacetylglutamine (PAG).
It has been observed that PAG is associated with risks of incident CVD in diabetic and non-diabetic subjects.
It was noted that PAG levels were significantly increased in subjects with end-stage renal disease (Meyer et al., 2016) And associated with mortality in one study (Shafi et al., 2015). Elevated urine levels of PAGln have also recently been associated with obesity (Elliott et al., 2015), Early decline in kidney function (Barrios et al., 2015, Poesen et al., 2016), And diabetes (Loo et al., 2018, Urpi-Sarda et al., 2019). Despite these reports, a mechanistic link between the pathogenesis of PAG and CVD has not been reported so far.
Dr Hazen said: “Over the past decade, a growing body of evidence suggests that gut microbes play a role in health, particularly with regard to heart disease.
“We have found that PAG blood levels contribute to the risk of cardiovascular disease in several ways.”
Analysis of samples from over 5,000 patients over three years found that elevated PAGln levels predicted subjects who would experience adverse cardiac events such as heart attack and stroke in the future, as well as those with type 2 diabetes. Studies in animal models and microbe transplants suggest that PAG produced by gut microbes may play an important role in driving cardiovascular disease.
The researchers also analyzed whole blood, platelet-rich plasma, and isolated platelets from patient samples to understand how PAG affects cellular processes. They then analyzed animal models of arterial injury to see how the cellular changes induced by PAG manifest in disease. Dr Hazen and his team found that PAG improved platelet reactivity and clotting potential, which increases the likelihood of blood clots, a major cause of unwanted heart events like heart attacks and strokes.
An overview of beta blockers
Dr Hazen, who also heads the Cleveland Clinic Center for Microbiome and Human Health, said: “Part of the reason we were so interested in making this discovery is that we found that PAG binds to the same receptors as beta blockers, which are drugs commonly prescribed to help treat heart disease. . “
Administration of beta-blockers to animal models with elevated PAG has been shown to reverse the cardiovascular parameters induced by PAG. Additionally, the researchers found that using gene editing technology or drugs to block PAG receptor signaling significantly reduced clotting activity.
“We believe our results suggest that some of the benefits of beta blockers can be attributed to the prevention of PAG-related activity,” Hazen said. “Beta blockers have been studied extensively and are prescribed to many heart patients, but to our knowledge this is the first time this mechanism has been suggested as an explanation for some of their benefits.”
Hazen. SL, et al
“Intestinal microbial metabolite linked to cardiovascular disease acts via adrenergic receptors”