Interplay of Cardiovascular, Sleep, and Gut Microbiome Systems in Heart Failure: Implications for Disease Progression and Management

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Heart failure (HF) is a progressive cardiovascular syndrome associated with low efficiency of the ventricle filling or ejection, with high hospitalization rates, significant morbidity and mortality, and rising healthcare costs. However, emerging scientific evidence indicates that HF is a multisystem disorder where sleep disorders and gut dysbiosis are not just comorbidities, but a dynamic and active component in the progression of the disease via interconnected inflammatory, neurohormonal and metabolic pathways. The purpose of this review was to provide an overview of the current knowledge about the role of the heart-sleep-gut axis in the pathogenesis and progression of HF and to highlight novel therapeutic approaches. In this review we search all English language and literature reviews from past 10 years on PubMed and Google Scholar. The 19 eligible studies were screened, assessed for quality, and narratively synthesized. The evidence shows a bi-directional link between HF and sleep disorders, such as OSA, CSA, insomnia and circadian rhythm disorders. Consequences of intermittent hypoxia and sleep fragmentation are sympathetic activation, endothelial dysfunction, inflammation, oxidative stress, arrhythmogenesis and HF-induced congestion and respiratory instability further disrupt sleep. At the same time, in HF, gut barrier dysfunction, due to hypoperfusion and edema, allows the translocation of bacterial components and toxic metabolites. High levels of trimethylamine N-oxide (TMAO) have been linked with atherosclerosis, thrombosis, fibrosis and adverse cardiac remodeling, while low levels of short-chain fatty acids (SCFAs) have been related to impaired epithelial integrity and anti-inflammatory signaling. Dysregulated bile acid metabolism also plays a role in metabolic and inflammatory dysregulations. Circadian, autonomic, and immune pathways can contribute to sleep disruption and consequently, gut dysbiosis can worsen sleep disruption and influence sleep regulation via microbiota metabolites. In a therapeutic setting, continuous positive airway pressure (CPAP) may be useful in certain cases, adaptive servo-ventilation is being investigated, behavioral sleep interventions, diet changes, probiotics, and gut microbial metabolites are possibilities that need to be evaluated. Combining sleep assessment and microbiome-targeted therapies into the management of HF could impact outcomes, but large, longitudinal studies are required to demonstrate causal relationship and precision therapies.