To the Editor, Restrictive cardiomyopathy (RCM) is a medical condition that manifests as diastolic dysfunction, thickening of the heart walls that is either normal or mildly increased, and sometimes severe enough to cause Kussmaul sign, which is an impaired rise of jugular veins during inspiration; additionally, congested liver, swollen legs, fluid in lungs, and eventually the collapse of the right heart chamber. Clonal hematopoiesis is prevalent in up to 10–20% of individuals aged 70–80 years and is associated with increased cardiovascular mortality, largely due to heightened risk of heart failure. There is already some softening evidence that RCM might be caused by clonal hematopoiesis of indeterminate potential (CHIP), characterized by mutations within hematopoietic stem cells resulting in not only the formation of clonal mutant white blood cell but also the presence of clones of pro-inflammatory myeloid cells, which are capable of causing inflammation and fibrosis in the heart1. RCM due to CHIP must be an inflammatory activity, similar to effusive-constrictive or tuberculous pericarditis, which, for that reason, is often not diagnosed due to being culture negative2. Hence, it usually remains underdiagnosed due to limited diagnostic tools for culture-negative cases, resulting in a great deal of morbidity. The phenylacetylglutamine-CHIP axis is not only the principal mechanistic axis of the condition but also the triggering factor and a possible diagnostic target. The gut-derived metabolite phenylacetylglutamine can lead to adrenergic hyperactivation and, through the synergy with CHIP, to myocardial fibrosis and RCM. The microbiota producing phenylacetylglutamine is the first modifiable initiator of the “inflammatory restrictive” phenotype. Probiotics targeting Akkermansia have been suggested to lower microbial creators of PAGIn to reverse this <90 case syndrome. Fetal metagenomics could be an analytical tool with a high yield that could uncover DNA of gut microbes, even in the case of culture-negative effusive-constrictive pericarditis. This therapeutic and diagnostic tool is relevant not only in the case of RCM induced by CHIP but also in effusive constrictive pericarditis, type 2 diabetes, obesity, metabolic syndrome, and intestinal inflammatory diseases3. Recent medical literature has shown that phenylacetylglutamine contributes to cardiac dysfunction. On examining two independent cohorts – 3256 people in the US and 829 in Europe – Romano et al showed a clear, dose-dependent interaction of elevated PAG in prevalent heart failure, independent of conventional cardiovascular risk factors and renal function. By demonstrating that phenylacetylglutamine directly impairs cardiomyocyte contractility, decreases sarcomere shortening, and increases natriuretic peptide gene expression, it proposes a pathophysiological role in myocardial dysfunction rather than a biomarker4. In another comprehensive clinical epidemiological study with 956 participants, Zong et al found that heart failure patients had significantly higher phenylacetylglutamine levels compared to non-heart failure patients. According to statistical modeling, the odds of heart failure increased by 50.7% for every standard deviation increase in PAG (OR 1.507; 95% CL 1.213–1.873), while the individuals in the harshest tertile exhibited more than double the risk of HF compared to the lowest tertile. With a 47.9% increase in cardiovascular mortality per 1-SD rise and a nearly twofold increase in cardiovascular death risk in the highest tertile (HR ≈ 2.049)5. Collectively, these findings provide strong epidemiological and mechanistic evidence that PAGln is tightly linked to heart-failure phenotypes and may contribute to cardiomyopathic progression. Though phenylacetylglutamine is becoming more widely acknowledged, there remain significant limitations. First, the majority of the evidence that is currently available is observational, and no interventional human studies have examined whether lowering PAGln improves cardiac outcomes, leaving causality unresolved4,5. Second, absolute PAGln concentrations vary across cohorts due to heterogeneous liquid chromatography with tandem mass spectrometry methods and population differences, and standardized reference ranges or prognostic cut-offs are lacking5,6. Third, the understanding of PAGln’s differential relevance is limited because most studies combine heart failure as a single entity with few phenotype-specific analyses (HFrEF vs. HFpEF; ischemic vs. non-ischemic)4. Fourth, therapeutic translation is limited by incomplete mechanistic work, which includes poorly defined cell-type specificity, downstream signaling, and myocardial dose kinetics7. Considering recent findings that point to the connection of gut-derived phenylacetylglutamine (PAGln) with myocardial fibrosis and diastolic dysfunction via CHIP interaction, the “restrictive cardiomyopathy” phenotype resulting from this modifiable gut-myeloid-heart axis becomes an overlooked but still very much reversible case of inflammatory cardiac restriction that can no longer be placed in the traditional infiltrative or idiopathic categories1,6,7. On the other hand, large cohort studies have provided strong evidence for a dose-dependent relationship between the rise in PAGln and the incidence of heart failure, progression, and cardiovascular mortality4,5, yet at this point, the particular subtype of heart failure with restrictive physiology is not being analyzed separately from the other subtypes since it is not yet established in the clinic. Also, the methods of quantification for the phenotype, the method of standardizing the quantification for clinical use, and the phenotype-specific analyses that the medical field lacks cannot be utilized in further studies, showing that either targeted reduction of microbiota that produce PAGln or direct blockade of its adrenergic signaling does not halt or reverse the process of myocardial stiffening. To speed up the translation process, researchers must focus on1 upcoming studies that will categorize PAGln levels and CHIP severity in cases of biopsy-proven or hemodynamically confirmed RCM, including culture-negative effusive-constrictive cases2; multilocation studies to standardize liquid chromatography-mass spectrometry methods and define reference ranges, as well as prognostic thresholds, through consensus; and3 clinical trials in early phases that will be testing microbiome-directed therapies, such as next-generation probiotics based on Akkermansia or dietary strategies restricting phenylalanine, alone and in combination with adrenergic modulators, in patients with the PAGln-CHIP inflammatory restrictive signature3,6,7, thus converting advantageous mechanistic pathways into practical diagnostic and therapeutic tools for a disease that still suffers from a long diagnostic process and a general lack of treatment options. This letter to the editor adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guideline8.
Kumar et al. (Fri,) studied this question.