Reconceptualizing restrictive cardiomyopathy as a modifiable gut–clonal hematopoiesis-inflammation axis

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 heart[1]. 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 negative[2]. 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