4.2. Interleukin-1 Antagonist
Meanwhile, other anti-inflammatory agents, apart from colchicine, were assessed for their cardiovascular effects. In the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trail
[47][17], 10,061 post-MI subjects with elevated CRP were enrolled. Targeting IL-1β with canakinumab markedly reduced the rate of recurrent cardiovascular events. Methotrexate, a widely used anti-inflammatory agent in rheumatological diseases, was evaluated but failed to improve the clinical efficacy of secondary prevention in patients with stable atherosclerosis. In the Cardiovascular Inflammation Reduction Trial (CIRT)
[48][18], 4786 individuals with previous MI or multivessel coronary disease, concomitant diabetes mellitus (DM), or metabolic syndrome were enrolled. At the 2.3-year follow-up, methotrexate did not reduce the composite rate of cardiovascular mortality, nonfatal MI, or nonfatal stroke. Anakinra-mediated IL-1 blockade has been evaluated for its clinical efficacy as a potential therapeutic target. Abbate et al. conducted a pilot study with 30 patients sustaining STEMI
[49][19]. The first dose of anakinra 100 mg was administered within 24 h of primary PCI and continued for 14 days. A significant decrease in serum CRP level and the rate of mortality or new-onset heart failure was documented, with no reduction in the level of CK-MB and MACE incidence.
5. The Role of Gut Microbiota
A disorganised profile of the intestinal microorganism was proposed to be interrelated with inflammation under the context of cardiovascular diseases
[60][20]. Amelioration of inflammatory status by modulating the gut microbiota composition is expected to serve as a new modality. Translocation of the microorganisms and shedding of the bacterial wall compound can contribute to the inflammatory status. Additionally, not only dysbiosis but also the altered metabolism gives rise to inflammation. First, the short-chain fatty acid generated by anaerobic fermentation of fibre is considered pivotal for initiating inflammatory signalling
[61][21]. Second, butyrate is another end metabolite of fermentation that had been identified to govern regulatory T cells for orchestrating inflammation and recognised prerequisite to maintain the intestinal barrier
[62][22]. A recent study with metagenome sequencing indicated the expression of the butyrate-encoding gene was negatively correlated with the level of inflammatory markers, which was proposed secondary to the altered abundance of
Roseburia and
Eubacterium in subjects with carotid atherosclerosis
[63][23]. Third, lipopolysaccharide (LPS) shed from Gram-negative bacteria was also pointed out as the bridge of remodeled microorganisms to inflammation and eventually attributing to the pathogenesis of cardiovascular diseases. The enteric LPS invades systemic circulation and ignites inflammation after being recognised by TLRs. The elevated endotoxin level and pro-inflammatory status eventually compromise cardiac and vascular function
[64][24].
Moreover, trimethylamine N-oxide (TMAO) was identified as another chief transmitter from dysbiosis to the inflammatory status impacting cardiovascular manifestations based on the metabolomic perspective. The quantity of TMAO was determined by age, body mass index, and especially the gut microbiome composition.
6. Gut-Cardio-Renal Triplet
Based on the accumulating evidence of mutual interplay, the triplet of the gut-cardio-renal axis was conceptualised to modify traditional cardiorenal syndrome (
Figure 21). The homeostasis of gut microbiota and its immunoregulatory effects are pivotal for maintaining the physiology of both the cardiac and renal systems. Regarding kidney physiology, impaired intestinal barrier function, microbial dysbiosis, compromised immunity, and toxin production were primary factors that correlated with altered gut microbiota and renal dysfunction
[87][25]. Short-chain fatty acids have been identified as key players in immune regulation, signalling of G-protein-coupled receptors, and antagonists of histone deacetylases for epigenetic modulation
[88][26]. Additionally, the pathogenesis of cardiorenal dysfunction implicates the effect of uraemic toxins, including indoxyl sulfate, p-cresyl sulfate, p-cresol, phenylacetic acid, indole-3-acetic acid, homocysteine, hippuric acid, and phenol
[89][27]. Collectively, the search for an upstream therapeutic target for better-integrated care remains a priority. Linaclotide, a guanylate cyclase C agonist, was identified as a potential candidate. Low-dose linaclotide was suggested to prevent and manage cardiorenal syndrome by downregulating plasma TMAO, uraemic toxin, and colonic claudin-1 levels
[90][28].
Figure 21. The gut-cardio-renal triplet. The gut microbiome and the pathophysiology of cardiac and renal systems are mutually interactive and dependent on the inflammatory response. TMAO: trimethylamine-N-oxide.
7. Conclusions
In conclusion, the residual inflammatory burden indicates a novel phenotype in patients with cardiovascular disease. In addition to traditional cardiovascular risk factors, the status of inflammation has been established to develop cardiovascular dysfunction, as well as compromise prognosis. With advances in
ourthe understanding of molecular networks, the generation of next-generation immunomodulatory agents specifically targeting new therapeutic targets identified via molecular investigations remains the current priority. Mechanism-based rationale to comprehend inflammation in the context of concomitant cardiovascular disease is currently the mainstream in bench studies. A better depiction of the interplay between inflammatory status and target organs constructed the gut-cardio-renal triplet. On the other end of the spectrum, future clinical trials with extended ethical backgrounds will facilitate the generalisation of these medications to orchestrate the inflammatory status from a clinical bedside perspective. Artificial intelligence with machine learning will be a novel modality for data mining and to assess the metabolome, transcriptome, and proteome. Specific management of signalling molecules will pave the way for individualised prescription and precision medicine.