Q&A: How a gut-derived metabolite may predict incidence, severity of HF
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Research suggests a potential mechanistic link between the gut microbiome and HF development, with new data demonstrating that levels of a gut-derived metabolite may track with HF risk and multiple indices of HF severity.
New research published in Circulation: Heart Failure shows an association between phenylacetylglutamine and HF risk persisted independent of CAD status and across the spectrum of HF phenotypes. In two cohorts of adults who underwent coronary angiography, researchers found that circulating phenylacetylglutamine levels were dose-dependently associated with HF presence and indices of severity, including reduced left ventricular ejection fraction and elevated N-terminal pro-B-type natriuretic peptide level, independent of traditional risk factors and renal function in both cohorts. Mechanistic studies also showed that phenylacetylglutamine and its murine counterpart, phenylacetylglycine, directly fostered HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction, in cultured cardiomyoblasts and murine atrial tissue.
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Stanley Hazen, MD, PhD, co-section head, preventive cardiology and rehabilitation, and director of the Center for Microbiome and Human Health at Cleveland Clinic, spoke with Healio about how a metabolite measurement could potentially predict HF, how drugs and diet changes might be able to help and the future of the gut microbiome in CVD.
Healio: Can you give our readers some background about this metabolite phenylacetylglutamine? What did we already know?
Hazen: Previously, we had looked for compounds in the blood of patients who did not have disease that predicted who would develop CVD in the future. For this compound, we were looking at people with diabetes, because heart disease is so prominent among people with diabetes. This compound, phenylacetylglutamine, or PAG, ended up being at the top of the list. In 2020, we reported in a paper that elevated levels of PAG predicted future risk for MI, stroke and death, not only in people with diabetes but also in people without diabetes, though PAG levels did tend to be even higher in people with diabetes. This compound was mediating this effect because it interacts with adrenergic receptors, the same reactors a beta-blocker interacts with. When we fed it to animals in preclinical studies, we saw we could promote clotting. In those studies, we also showed if you gave a beta-blocker, it would block the diseased phenotypes we were seeing.
This compound comes from protein from our diet and is generated by the microbes in our intestines. Chronic exposure to it — whether from eating lots of protein or whether someone has more of the microbes — would predispose to the development of CVD.
What led you and your colleagues to conduct this research on PAG and HF?
Hazen: Given how closely linked adrenergic receptors are with HF, that made us want to focus on looking at levels of this compound and see if it could predict the incidence, severity and type of HF. Was there a mechanistic connection between this compound and the development of HF? That is what this paper shows. Among patients, a higher PAG level predicted risk for HF and type of HF and would mediate effects that made it look like it was contributing to many of the symptoms seen with HF.
What might be the next research steps?
Hazen: There are many. One of things we need to find out is how do we turn this into actionable interventions to treat patients? Immediately, these results further emphasize how this marker could be a good diagnostic blood test. It is independent, additive and as strong as all the current best blood tests that we use — and there are not many — for HF.
We want to expand and evaluate its role as a diagnostic.
Additionally, given our animal model studies form before, the natural next step would be, in humans, to see if subjects with a high PAG level did well when placed on a beta-blocker. One of the biggest risk factors for HF is hypertension. I would argue the present data suggest that if you have a high PAG level, you might have a better outcome by using a beta-blocker vs. an alternative BP medication.
PAG is produced from protein in the diet. Protein, whether coming from animal-sourced or plant-sourced foods, the phenylalanine level is the same. In general, if you eat a more vegetarian diet, a person consumes less protein vs. an omnivore. The research suggests that reducing protein intake via diet changes could help to lower PAG levels.
What does this research add to our understanding of the gut microbiome?
Hazen: I have been doing this work for more than a decade. I have become a believer in the concept that the gut microbiome will have a tremendous impact on our health. The single biggest foreign object is not pesticides or pollution in the air, it is what we eat. The bottom line is the filter of that exposure is our gut microbial community. Even two identical twins will experience the same meal differently and generate different constellations of metabolites. This is, when you talk about personalized medicine, this is where it needs to go.
I am convinced we will have therapeutics targeting microbial pathways for treating all of these common diseases, including HF, that do not kill the bacteria — not antibiotics. We can become much more selective.
The take-home message for patients at this point is there is great progress that is advancing our understanding of new pathways linked to HF development.
Reference:
Romano K, et al. Circ Heart Fail. 2022;doi:10.1161/CIRCHEARTFAILURE.122.009972.
For more information:
Stanley Hazen, MD, PhD, can be reached at hazens@ccf.org.
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