Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Abstract

Heart failure (HF) patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive pulmonary disease, and chronic kidney disease. The coexistance of comorbidities usually leads to multi morbidity and poor prognosis. Treatments for HF patients with multi morbidity are still an unmet clinical need, and finding an effective therapy strategy is of great value. HF can lead to comorbidity, and in return, comorbidity may promote the progression of HF, creating a vicious cycle. This reciprocal correlation indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital role in the pathophysiological processes of HF and comorbidities, indicating metabolism and inflammation may be the links between HF and comorbidities. In this review, we comprehensively discuss the major underlying mechanisms and therapeutic implications for comorbidities of HF. We first summarize the potential role of metabolism and inflammation in HF. Then, we give an overview of the linkage between common comorbidities and HF, from the perspective of epidemiological evidence to the underlying metabolism and inflammation mechanisms. Moreover, with the help of bioinformatics, we summarize the shared risk factors, signal pathways, and therapeutic targets between HF and comorbidities. Metabolic syndrome, aging, deleterious lifestyles (sedentary behavior, poor dietary patterns, smoking, etc.), and other risk factors common to HF and comorbidities are all associated with common mechanisms. Impaired mitochondrial biogenesis, autophagy, insulin resistance, and oxidative stress, are among the major mechanisms of both HF and comorbidities. Gene enrichment analysis showed the PI3K/AKT pathway may probably play a central role in multi morbidity. Additionally, drug targets common to HF and several common comorbidities were found by network analysis. Such analysis has already been instrumental in drug repurposing to treat HF and comorbidity. And the result suggests sodium-glucose transporter-2 (SGLT-2) inhibitors, IL-1β inhibitors, and metformin may be promising drugs for repurposing to treat multi morbidity. We propose that targeting the metabolic and inflammatory pathways that are common to HF and comorbidities may provide a promising therapeutic strategy.

Keywords: chronic inflammation; comorbidities; heart failure; metabolism; mitochondria; reactive oxygen species.

Figure 1

The estimated prevalence of heart failure comorbidities in different organs and systems.

Figure 2

An overview of normal physiological metabolic processes and the pathological metabolic remodeling characteristic of HF. Blue arrows show normal cardiac metabolic processes. The altered metabolic processes of HF are displayed in red; Arrows indicate changed metabolic intermediates and products. TCA, tricarboxylic acid; BCCA, branched-chain amino acids; BCKA, branched-chain alpha-keto acids; ROS, reactive oxygen species; NCX, Na⁺/Ca²⁺ exchanger.

Figure 3

Analysis of common genes and pathways in comorbidities and HF. (A): Venn diagram of common genes between comorbidities and HF; (B): Dot plot of top 20 enriched Gene Ontology biological processes enriched for common genes between HF and comorbidities; (C): Dot plot of top 20 enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways for common genes between HF and comorbidities; (D):Dot plot of top 20 enriched transcription factors from TRRUST(Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining) database.

Figure 4

Main possible shared mechanisms underlying HF and comorbidities. HF, comorbidities, and risk factors may have some shared chronic conditions such as insulin resistance, hypoxia, and chronic inflammation, these conditions aggravate HF and cause comorbidities. The mechanism of comorbidities contribute to HF can be clarified similarly. Cardiac energy metabolic remodeling may take place in these conditions mediated by activating the AMPK signaling. Metabolic remodeling can activate PI3K/AKT pathway, which promotes myocardial over-growth and cardiac hypertrophy and can cause mitochondrial injury. The mTOR signaling may be activated by AMPK and PI3K/AKT pathways can cause disturbed autophagy which aggravates the mitochondrial injury. Ischemia and hypoxia conditions can activate MAPK and HIF-1 pathways, which contribute to cardiac structure remodeling. Innate immune cells, mainly monocytes, macrophages, and neutrophils, can trigger the immune response and systemic inflammation by secreting IL-1β and IL-6. Moreover, the pro-inflammatory cytokines stimulate T cells to polarize to Th17 cells and release IL-17. Systemic inflammation can cause diastolic dysfunction and cardiac hypertrophy.

Figure 5

Abridged common drug target network of heart failure and comorbidities.