Thorac cardiovasc Surg 2014; 62(07): 543-546
DOI: 10.1055/s-0034-1377064
Letter to the Editor
Georg Thieme Verlag KG Stuttgart · New York

Fat and the Heart: A More and More Complex Interplay

Stefan Dhein
1  Clinic for Cardiac Surgery, Heart Center Leipzig, University Leipzig, Leipzig, Germany
› Author Affiliations
Further Information

Publication History

20 March 2014

21 March 2014

Publication Date:
25 June 2014 (online)

An emerging new topic in cardiovascular science is the possibility of a pathophysiological role of fat cells and their mediators in cardiovascular disease, particularly for atrial fibrillation (AF), apart from the general finding that overweight is associated with several cardiovascular disorders. Nearly 26 years ago, obesity was reported as a risk factor for postoperative AF,[1] which was also found by others.[2] While this was a more coincidental observation without a molecular pathophysiological explanation, today evidence is growing that adipokines released from fat cells might influence cardiac myocytes and in particular cardiac electrophysiology.

Thus, it was recently[3] shown that incubation of left atrial cardiomyocytes, which were incubated with isolated fat cells for 2 to 4 hours, had longer action potentials and a more depolarized resting membrane potential. In that study, it was shown that coincubation with adipocytes (from epicardial fat) caused larger late sodium currents, enhanced L-type calcium currents, and transient outward K+ currents, but reduced delayed rectifier and inward rectifier K+ currents.[3] In addition, these authors showed that the inducibility of triggered beats following adrenergic stimulation was enhanced in adipocyte coincubated atrial cardiomyocytes.

AF and obesity have been reported to be associated.[4] [5] However, the pathophysiological processes behind this association are widely unclear. Thus, AF typically is associated with a remodeling process leading to chronification and to stabilization of AF. Typical findings are, for example, atrial fibrosis,[6] reduced expression of L-type Ca2+ channel,[7] altered Ca2+ handling,[8] [9] altered other ionic currents,[10] connexin remodeling with enhanced expression at the lateral cell border, and enhanced transverse conduction.[11] [12] These processes lead to inhomogeneities of propagation and shortened action potentials thus favoring and stabilizing AF.

With regard to a possible pathophysiological role of fat cells that could explain the positive correlation between obesity and AF, in stable anticoagulated nonvalvular AF patients, low adiponectin levels were found to be associated with major cardiovascular events in females.[13] In the Framingham Study Offspring, Rienstra et al[14] detected a correlation between incident AF and plasma resistin, while association was attenuated when adjusted for C-reactive protein, and adiponectin did not correlate with incident AF. Other investigators, however, found a significant correlation between adiponectin levels and the presence of persistent AF.[15]

In the present issue, two articles focus on an independent role of body mass index (BMI) in AF, one addressing chronic AF[16] and the other postoperative AF (POAF).[17] Another recent article was on the role of the adipokine resistin in advanced atherosclerosis.[18] Regarding AF, Tadic et al[17] found that out of 460 patients (who had no history of AF episodes) undergoing coronary bypass surgery, 103 developed POAF. These patients were significantly older, in majority male (73%), and significantly more often exhibited criteria of a metabolic syndrome. Regarding the latter, these authors[17] showed that, in particular, increased BMI and enhanced abdominal fat seem to be associated with increased incidence of POAF. In addition, they determined major adverse cardiovascular and cerebrovascular event (MACCE) rate for a 3-year follow-up. MACCE also seemed to be positively associated with obesity in this study. Regarding causality one could critically mention that with increasing age, incidence and severity of the metabolic syndrome as well as obesity might be more pronounced. These POAF patients were nearly 6 years older. However, against this critical view is the other article,[16] in which the authors show that increased BMI is associated with changes in the atrial cell biology in sinus rhythm and to a higher extend in chronic AF (valvular disease associated): in atrial cardiomyocytes, the gap junction protein connexin43 was increased at the lateral border in those patients with BMI > 27, even in sinus rhythm. More clearly, these changes were evident in AF patients' cells with strongly elevated lateral connexin43 in patients with BMI > 27. The lateralization of connexin43 can be seen as a factor which favors transverse conduction and thereby making the atrium more prone to the occurrence of small reentrant circuits and AF.[12] Interestingly in comparison with the other study,[17] in the study by Rothe et al,[16] the two groups of AF patients (with BMI either < 27 or > 27) were not significantly different with regard to age, gender, hypertension, tallness, left atrial diameter, comorbidity, and drug treatment. These authors came to the conclusion that BMI independently affects remodeling processes in the atrium, which favor AF and enhance AF-associated remodeling. Taken together, both studies underline the importance of BMI as a risk factor for different forms of AF and that this probably acts as an independent factor. If so, the next question would be how BMI or abdominal obesity might lead to cellular changes in atrial cardiomyocytes. In that context, adipokines could play a role. Adipokines comprise a group of mediators ([Table 1]), all released from fat cells (for review, see Northcott et al[19]).

Table 1

Survey about some effects of various adipokines

Adipokine

Function

Cardiovascular function

Resistin

Suppresses insulin signaling, inhibits glucose uptake, promotes TNFα secretion

Endothelial cells: impairs endothelium-dependent relaxation, increased VCAM and ICAM expression, decreased NOS expression

VSMC: promotes proliferation/migration

Cardiomyocytes: decreased glucose uptake, hypertrophy, ROS production

Leptin

Controls appetite, and enhances IL-6, TNFα, and VEGF

Endothelium:

Acute effect: endothelial angiogenesis, NO production

Prolonged effect: endothelial ROS production

VSMC: enhanced proliferation

Cardiomyocytes: hypertrophy, reduced contractility

Cardiac fibroblasts: fibrosis

Adiponectin

Reduces IL-6, TNFα, and ICAM-1

Enhances IL-10 and IL-1

Endothelium:

Differentiation of endothelial progenitor cells to endothelial cells, endothelial PGE2 production

VSMC: inhibition of VSMC

Cardiomyocytes: enhances glucose and fatty acid metabolism, blocks resistin effects on ICAM expression

Cardiac fibroblasts: promotes cardiac fibrosis

Adipsin

Complement factor D, regulation of de novo triglyceride synthesis, and reesterification in adipocytes

Function in cardiovascular system unclear

Chemerin

Adipocyte differentiation, adipogenesis, proinflammatory, chemoattractants

Endothelial cells: proangiogenic

Omentin

Fat depot specific

Regulates body fat distribution

Endothelial cells: increased NOS activity, increased angiogenesis

VSMC: prevents osteoblastic differentiation

Cardiomyocytes: cardioprotective actions

Vaspin

Insulin-sensitizing effects

Suppression of leptin, resistin, adiponectin, and TNFα

VSMC: inhibits hyperglycemia-induced proliferation

Visfatin

Insulin-mimetic effects, IL-6, and IL-8 upregulation

Endothelial cells: angiogenic effects, enhanced NOS expression, E-selectin

VSMC: iNOS expression, proliferation

Cardiomyocytes: antiapoptotic

Lipin

Phosphatidate phosphatase enzyme, regulation of intracellular TAG storage

Function in cardiovascular system unclear

Abbreviations: ICAM, interstitial cell adhesion molecule; NOS, nitric oxide synthase; ROS, reactive oxygen species; TAG, triacylglycerole; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.


Note: It needs to be mentioned that most of these effects are described in mice and rats.[19] [20] [21] [22] [23] [24] [25] [26] [27] [28]


As can be seen from [Table 1], some of the adipokines exert opposite effects, and the resulting net effect will depend on the mixture of adipokines released. This, however, seems to depend on the type of fat cells and on the body status, that is, the presence or absence of obesity. It seems that obesity results in a shift of adipokine profile toward a more proinflammatory profile.[19] Among these adipokines, recent research paid much attention to resistin as a adipokine related to insulin resistance and metabolic syndrome.

Resistin has been found to be increased in epicardial adipose tissue of patients with a history of myocardial infarction and advanced coronary atherosclerosis,[18] which is in good accordance with Rienstra et al.[14] Interestingly, Rachwalik et al[18] found that the resistin level in epicardial fat and fat cells around the internal mammary artery was elevated in patients with a history of myocardial infarction, while this was not the case in subcutaneous fat. This finding points to the idea that fat cells may differ in their autocrine profile with regard to their location. While visceral, subcutaneous, and abdominal can act on cardiovascular cells via endocrine mechanisms, epicardial fat can influence cardiomyocytes and cardiac fibroblasts in a paracrine fashion because epicardial fat is not separated from myocardium by fascia-like structures. Similarly, perivascular fat cells also can act in a paracrine manner on vascular smooth muscle cells and fibroblasts.

Different fat cells seem to produce different profiles of adipokines. Thus, it has been described that in obesity, fat cells become dysfunctional with a shift toward secretion of more proinflammatory adipokines (see [Table 2]). Moreover, differences seem to exist between white and brown fat cells, subcutaneous, visceral, epicardial, and perivascular fat cells. However, these differences and their physiological meaning are presently not understood. One could imagine that either the types of adipokines being released from a certain type of fat cells might differ or that the receptors on the surface of the fat cells and the signal cascades might differ among the various fat cell types. Moreover, it has been suggested that the profile of adipokines may vary when visceral fat increases and may be more proinflammatory. Thus, in obesity, fat cells exhibit a so-called dysfunctional type.

Table 2

Survey about the adipokines released from various types of fat cells[19] [20] [21] [22] [23] [24] [25]

Normal fat cells

Dysfunctional fat cells (in obesity)

Anti-inflammatory adipokines

↑ Adiponectin, omentin

↓ Adiponectin, omentin

Proinflammatory adipokines

↓ Leptin, chemerin, visfatin, resistin

↑ Leptin, chemerin, visfatin, resistin

In that context, recent articles[16] [17] [18] indicate that obesity or increased BMI exert own independent effects on the heart, in particular on the atrium, and may open the perspective for future research which should be directed toward the identification of the adipokines involved and the molecular signaling mechanisms behind the changes in atrial remodeling.