The failing of the obesity paradox in the failing heart

OBESITY IS DETRIMENTAL FOR THE HEART

The prevalence of obesity is increasing worldwide. Obesity-related metabolic disorders are at the center stage to the development of heart disease, stroke, type 2 diabetes, and certain types of cancer, leading to a reduced quality of health and economic burden (3). In the United States, >40% of adult men and women are obese. These same patients have additional risk factors such as hyperglycemia and hypertension that are associated with cardiometabolic defects including heart failure (HF) (4, 5). According to the Framingham Heart Study, being overweight and obese remains the primary cause and risk factor for the development of HF, accounting for a 5% increase in men and a 7% increase in women for the risk of developing HF per unit of body mass index (8). As highlighted in previous reports, excessive adipose tissue accumulation impacts hemodynamic function, cardiac morphology, adipocytes, and cytokines, which leads to diastolic and/or systolic dysfunction and hypertrophy (4). However, even less is known about pathophysiological basis of sex-specific and age-related cardiac remodeling in HF. In obesity, fat mass, particularly visceral fat, has subsequent effects including insulin resistance and thereby hyperglycemia and type 2 diabetes. In fact, obesity contributes to the development of low-grade chronic inflammation and inflammatory cytokine production. This low-grade inflammation leads to an impairment in insulin signaling; however, not all forms of fat intake or obesity are equal in insulin resistance (6). Due to the enormous heterogeneity of obesity and HF, contrasting reports have indicated that obesity paradoxically confers a better outcome in HF. Conflicting studies have shown that overweight patients with HF have a better survival rate than underweight patients with HF (9). The reason behind this paradox remains unclear, but there are novel hypotheses and data that partially explains that collider bias is the reason for the confounding factors. One of the potential reasons for the obesity paradox is that the lipid mediators/metabolites that are in reserve in circulatory blood bind to endotoxins/leukocyte receptors and inhibit their harmful effects. The other reason is that progressive HF is a catabolic state; thus, a greater metabolic reserve would be helpful in obese patients with HF (2, 9).

AGE-RELATED CARDIAC HEALTH IN OBESITY AND DIABETIC MALE AND FEMALE SUBJECTS

Taken together with past reports, Alex and colleagues (1) performed an elegant and comprehensive study in a recent issue of the American Journal of Physiology-Heart and Circulatory Physiology. The presented cardiac phenome study addressed a systematic analysis of the sex-specific functional, structural, and fibrotic myocardial alterations in obesity-prone db/db mice. The authors used a db/db monogenic mouse model with a spontaneous mutation of the leptin receptor that develops phenotypes of severe obesity, hyperphagia, hyperglycemia, and polyuria. Use of obese, hyperglycemic, and diabetic mice recapitulates certain aspects of human obesity-related HF with preserved ejection fraction (HFpEF) and diastolic dysfunction (Fig. 1). Compared with male db/db mice, female db/db mice were prone to mild hypertension and increased cardiac hypertrophy with profound vascular remodeling in the absence of systolic dysfunction. However, only male db/db mice exhibited significant microvascular rarefaction. Both male and female mice had evidence of diastolic dysfunction, cardiomyocyte hypertrophy, and increased perimysial collagen thickness and higher endomysial collagen content. Furthermore, other exciting results from this study were that isolated cardiac fibroblasts from both male and female db/db mice had increased baseline expression of collagen but exhibited blunted responses to transforming growth factor (TGF)-β stimulation. Interestingly, use of the monogenic db/db mouse model showed signs of vascular fibrotic remodeling with collagen deposition without fibroblast-to-myofibroblast differentiation. These data suggest an alternative novel mechanism of microvascular remodeling in the db/db mouse model of HFpEF (1). These temporal findings in male and female mice could provide novel insights in the understanding of the cellular and molecular basis of cardiac remodeling and dysfunction in obese, hyperglycemic, and type 2 diabetic subjects having signs of HF with preserved systolic function. The presented temporal dynamics open a new avenue in preclinical HF research for age-dependent function and structural alterations in cardiac health.

Fig. 1.

Cardiac health in obesity and diabetes. Temporal key determinants of cardiac phenome study in obese and diabetic mice clearly indicate that prime aspects of cardiac health are defective leading to hypertension, diastolic dysfunction, and vascular pathophysiology. Future investigation of the temporal proteome, lipidome, metabolome, and immunometabolome would be of interest to determine the clinical utility of this heart failure mouse model.

IS PROTEOMIC, LIPIDOMIC, METABOLIC, AND IMMUNE PROFILING ALTERED AND TEMPORALLY DEFECTIVE IN OBESE AND DIABETIC MICE?

In translational rodent research, there is an ongoing debate of using “monogenic” versus “polygenic” mouse models because no single obesity and diabetic animal model recapitulates all the molecular and cellular features, biomarkers, or integrative metabolic complications of human HF. In the clinical setting, HF depends on the degree of obesity, comedication, smoking, action/inaction, dysregulation of the circadian clock, diabetes, islet atropy/hypertrophy, aging, cardiometabolic defects, and immune dysfunctional complications (4). Emerging technology with advancements of quantitative methods using mass spectrometry and identification of multiple “ome” is under investigation to define cardiac metabolism in HF. Based on cardiac phenome observations, the following four omes (proteome, lipidome, metabolome, and leukocytome) will likely identify the derangements in the preclinical model of HFpEF.

First, in cardiovascular proteomics, the quality and quantity of data are growing exponentially in preclinical and clinical research. Proteomics outcome provides important insights into protein modifications that regulate function and activity of enzymes and other proteins, because it can identify binding sites for specific protein interaction from mapping and quantification of protein identities, abundances, and posttranslational modifications (10). Therefore, it would be useful to investigate whether the protein ontological categorization and functional enrichment in db/db male and female subjects are comparable or contrasting compared with humans to define the clinical utility of this model. Second, the lipidome is composed of >40,000 hydrophobic or amphipathic lipid species with precise structural and biological properties. In particular, biosynthesis of specialized proresolving mediators is severely dysregulated in inflamed obese adipose tissue and aging mice after the cardiac injury model of HF (4). The deficiency of proresolving mediators in adipose tissue in obesity could be the consequence of vascular structural deficiency due to tissue content of polyunsaturated fatty acids as established substrates for resolution metabolome (4). Quantitative measurements of resolution mediators with metabolic flux technology with the novel concept of resolution of inflammation research endeavors will be translational to make progress in controlling metabolic dysfunction and chronic inflammation. Third, the metabolome data showed that neurohormonal and metabolic alterations are significant during the entire process of obesity-related HF progression (7). In addition to its potential utility in HF diagnosis, metabolic profiling may be useful in identifying patients at increased risk for HF development. Much less is known about how to counterregulate metabolic alterations in obesity-associated HF and limit metabolic signaling or survival. Finally, leukocyte profiling with metabolome (leukocytome or immunometabolome) in the context of heart injury has ramped up during these last years, and researchers are providing evidence of the importance of immune cell modulation as a crucial factor for inducing cardiac repair (4). With this prominent comprehensive cardiac phenome study, Alex and colleagues have added new insights into obesity and diabetes research. Additional molecular and cellular signaling will confirm the translational utility of this model for the screening of novel human therapeutics.

CONCLUSIONS AND FUTURE DIRECTIONS

Age-dependent functional, structural, and fibrotic microvascular alterations are key determinants of cardiac health in obese and diabetic male and female mice (Fig. 1). Female db/db mice are more prone to hypertension than male db/db mice. The presented study has added age-dependent novel, comprehensive, and precise changes in an obese and diabetic mouse model to study diastolic dysfunction with vascular and fibrotic remodeling. How the proteomic, lipidomic, metabolic, and leukocyte-dependent molecular signals advance the vascular and fibrotic remodeling with preserved systolic function remains unknown. Studies aimed to define the impact on immunometabolism with advancement of diastolic dysfunction with preserved systolic function are critical to discover and develop novel targets in human HF.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

B.T. and G.V.H. drafted manuscript; G.V.H. conceived and designed editorial; G.V.H. prepared figure; G.V.H. edited and revised manuscript; G.V.H. approved final version of manuscript.