Unraveling the mechanisms linking obesity and heart failure: the role of adipokines

The intriguing nature of the association between obesity and heart failure (HF) has led to great interest from a research, clinical and drug discovery perspective, but also to many controversies and uncertainty in the mechanistic understanding of disease pathogenesis [1].

As is widely appreciated, obese individuals are more likely to suffer myocardial infarction (MI), yet many studies now also indicate that post-MI event-free and survival time may be improved in obese individuals, which is known as the so-called obesity paradox [2]. There are many potential contributors to this interesting phenomenon:

• • Assessment of obesity, which itself is a heterogenous disorder, and body fat distribution – a significant contributor, with excess visceral abdominal fat conferring a higher risk of HF [3];

• • The degree of obesity, for example, comparing overweight to morbidly obese, may determine the impact on cardiac remodeling [1];

• • Multiple myocardial remodeling events (including changes in metabolism, cell death and fibrosis) can be responsible for contractile dysfunction in HF [1], and these are likely to vary considerably from one individual to another;

• • Another confounding component in our understanding of HF is the progressive nature, which may span several decades. Thus, the age or length of time an individual has been obese may be important determining factors in understanding disease pathogenesis;

• • The significance of managing diabetes in HF has long been a topic of intense interest and debate, and the frequent coexistance of diabetes may further contribute to determining the impact of obesity per se on HF [1].

Another important consideration in deciphering the available literature toward a unifying consensus is that translation of the extensive research using animal models to human relevance is indubitable [4]. Animal models are certainly an excellent tool in many instances but caution must always be exercised when extrapolating these studies to human significance since many features of HF differ between rodents and humans. For example, many commonly used models feature extreme physiological instances of complete lack or overexpression of a hormone (see later). Furthermore, epicardial fat can be a marked characteristic of human obesity, yet is not replicated in rodents.

How does an alteration in adipose tissue mass or distribution impact heart function? To answer this question, recent years have seen an intense focus on understanding the contribution of various adipokines that are secreted from adipose tissue and may mediate endocrine effects on the myocardium [5]. A brief summary and perspective on the contribution of two principal adipokines, adiponectin and leptin, to HF pathogenesis is given later. With respect to the heart, two additional interesting concepts must be highlighted. First, there is often a substantial accumulation of epicardial fat in obese humans (but not small animal models), which is now known to have visceral fat-like characteristics and may release adipokines to mediate paracrine effects on the myocardium [6]. Second, the heart itself can synthesize adipokines and, for example, many studies have documented alterations in cardiac adiponectin levels coincident with HF and independent from plasma levels, most notably in humans [7].

Adiponectin is unlike many adipokines in that circulating levels decrease in obesity, and adiponectin has now been shown to elicit many cardioprotective effects [8–10]. A surge in studies examining the correlation between the decreased plasma adiponectin levels observed in obese individuals and various cardiovascular outcomes has established adiponectin as an independent risk factor for various cardiovascular disorders. Particular attention should also be paid to specific changes in the various oligomeric forms of adiponectin [11] and, in particular, local concentrations in the myocardium, since these are likely to mediate a number of distinct effects on the myocardium. Numerous studies in adiponectin-knockout mice have convincingly demonstrated exacerbated detrimental effects upon ischemia reperfusion- or pressure overload-induced MI. Remarkably, adiponectin administration (injection of recombinant protein or adenoviral delivery) before, during or even after MI can prevent the exaggerated remodeling in these mice. The consensus is, therefore, that adiponectin confers cardioprotection and is a viable therapeutic target. Importantly, based on evidence to date, this is likely to largely hold true from mice to humans. To mediate beneficial effects, adiponectin is known to regulate remodeling events leading to changes in cardiomyocyte substrate metabolism, cell death, hypertrophy and fibrosis [1,9,12]. A potentially important protective mechanism is the ability to prevent excessive reactive oxygen species (ROS) generation, perhaps via enhancing antioxidant defense mechanisms while insulin-sensitizing effects may also be significant [13]. An important concept not yet widely accepted is the existence of myocardial adiponectin resistance in HF patients [14]. This may be especially relevant in determining the interplay between obesity and diabetes in HF, since hyperglycemia is one avenue via which adiponectin resistance may ensue [15].

Many studies have proposed leptin as a potential link between obesity and HF [16–18]. Much of our knowledge on the role of leptin in HF has been derived from obese animal models lacking leptin or exhibiting defects in leptin action. As alluded to previously, it must be borne in mind that cases of human obesity resulting from lack of leptin are extremely rare and there is, in fact, a positive correlation between plasma leptin and BMI, while the existence of peripheral leptin resistance in the majority of obese individuals remains contentious. Indeed, the enticing concept of selective leptin resistance (i.e., distinguishing hypothalamic from myocardial leptin signaling) was raised many years ago but has yet to be conclusively established [19]. Hence, the distinction between normal physiological effects of leptin on the heart and pathophysiological effects ensuing in a hypo/hyperleptinemic- or leptin-resistant milieu is an important matter that has yet to be adequately resolved. As with adiponectin, there are now several reports indicating local production of leptin in the heart, and research to establish auto/paracrine effects should be encouraged. Mechanistically, metabolic regulation by leptin is a key determinant of direct effects on cardiac function, with the ability of leptin to prevent lipid-induced cardiac dysfunction being one important feature [20]. Effects on ROS, the extracellular matrix, cardiomyocyte hypertrophy and apoptosis may also be important direct contributors [12,18]. Overall, there is no doubt that leptin can directly regulate various parameters of cardiac remodeling in model cells, tissues or animals. However, further efforts should be directed toward ascertaining the more debatable physiological relevance in humans.

Biomarkers for HF continue to emerge and be validated. Of particular relevance here is adiponectin, and clear criteria for their use in effective diagnosis of HF type may contribute greatly to preventive medicine [21]. Recent years have seen growing emphasis on personalized medicine in many disease areas, particularly oncology, and this is also an attractive future addition to the cardiologist’s armory to fight obesity-related HF [22]. A carefully coordinated comprehensive clinical analysis (potentially ranging a wide spectrum from genomics to noninvasive imaging) designed to subclassify type of HF based on underlying pathogenesis may make this possible. Currently, physical activity and improved nutritional habits provide a strong foundation for effective therapy, traditional and novel pharmacologic approaches continue to be applied [23] (including the potential of targeting adiponectin [10,24]), and emerging approaches, such as stem cell therapy, are exciting developments [25].

In summary, unraveling the mechanisms linking obesity and HF is clearly not a straightforward task. Obesity and concurrent changes in adipokine profiles can influence cardiac remodeling both directly and via commonly associated comorbidities. The consequent interplay of multiple remodeling events occurs over a particularly long period of time, and the extent of any particular aspect of remodeling will probably vary at distinct stages in the progression of HF. Furthermore, these events can remain undetected for decades before clinical manifestation and may even differ significantly between individuals with similar cardiac dysfunction. Ideally, clearly understanding the mechanistic basis of cardiac remodeling in obesity, particularly their temporal nature and the role of adipokines, may allow more efficient diagnostic approaches to identify the most appropriate therapeutic approach on a case-by-case basis.

Acknowledgements

There is a vast volume of literature of outstanding original articles that, regrettably, could not be cited here due to space restrictions.

Financial & competing interests disclosure

Work in the author’s laboratory is funded by the Canadian Institutes of Health Research and Heart & Stroke Foundation of Canada. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.