Novel Insights Into the Pathogenesis of Obesity-Related High Output Heart Failure From Gene Expression Profiling

The prevalence and high mortality rate of cardiac diseases, which inevitably lead to heart failure, necessitate an exhaustive description of the human heart. However, this has been substantially hampered by the cellular heterogeneity of cardiac tissues and restricted sample access.1, 2) Transcriptome analysis is a powerful tool that helps elucidate heart failure and develop new treatments for this devastating disease. Recent studies employing transcriptome analyses have yielded abundant reference data on cell types and interaction networks in the adult human heart.3, 4)

Although the obesity paradox is a growing concern,5) obesity is a well-known risk factor for several cardiovascular diseases. Obesity is the leading cause of certain types of heart failure, including high-output heart failure (HOHF). HOHF is characterized by high cardiac output, decreased systemic vascular resistance, and increased oxygen consumption.6, 7) Increased insulin resistance, increased levels of vasoactive adipokines, and alterations in adipokines (increased levels of leptin and neprilysin, and decreased levels of adiponectin) are possible pathophysiologies of HOHF associated with obesity.8) Transcriptome analysis may provide greater knowledge of HOHF and diagnostic clues for the disease.

In the latest issue of the International Journal of Heart Failure, Cintron et al.9) conducted a pilot and cross-sectional study to examine the variances in leukocyte transcriptomes of morbidly obese patients with HOHF and attempted to provide insight into the underlying pathophysiologic mechanisms. Gene expression analyses showed the upregulation of 114 genes and downregulation of 2 genes in morbidly obese and HOHF patients compared to the gene expressions in morbidly obese and non-HOHF patients. The most upregulated canonical pathways were associated with autophagy, adenosine monophosphate-activated protein kinase signaling, and senescence pathways. Using a network analysis, the authors identified GATA binding protein 1 as an upstream regulator and nuclear factor kappa-light-chain-enhancer of the activated B cells associated network.

The pathophysiological mechanisms that contribute to the pathogenesis of obesity-related HOHF are not fully understood. Insufficient evidence exists to guide the clinical management of the affected patients, which are distinct from general “heart failure.”10, 11) To develop interventions that alleviate patient symptoms and enhance health outcomes, additional research must address the mechanisms underlying HOHF. Transcriptome analysis can contribute to a systemic level understanding of the molecular abnormalities that contribute to HOHF pathogenesis in obese patients.3, 4) Although research on myocardial metabolomics in patients with heart failure and preserved ejection fraction with severe obesity and diabetes has been conducted employing transcriptome analysis,12) no studies have attempted to evaluate the cellular characteristics of HOHF using transcriptome analysis. This study provided insights into the cellular basis of cardiac homeostasis and heart failure, as well as potentially useful information for the treatment of HOHF associated with obesity.

This study had some limitations. First, the authors proposed a connection between the leukocyte transcriptome and systemic inflammation and suggested that this may be associated with the initiation and progression of heart failure. However, as this was the first study to identify certain gene expressions that distinguish obesity-related HOHF from non-HOHF, evidence for an association between the leukocyte transcriptome and heart failure initiation and progression remains inconclusive. Second, compared to previous studies on gene expression profiling in HF patients,4, 12) although this was a pilot study, the number of patients enrolled was exceedingly small, and their baseline characteristics differed widely. This makes it challenging to determine the significance of differences between obesity-related HOHF and non-HOHF leukocyte transcriptomes.

Taken together, this study provided valuable insights into the gene expression changes associated with obesity-related HOHF, uncovering the potential molecular pathways and mechanisms involved in this condition. These findings pave the way for further investigations aimed at a better understanding and management of this specific phenotype of heart failure.