Background
Obesity is recognized as one of the major drivers of the increasing prevalence of cardiovascular disease worldwide. Importantly, obesity, independent of conventional risk factors and myocardial infarction, is a risk factor for several cardiovascular events including the progression to heart failure [
1‐
3]. Insulin resistance may be a factor which mediates obesity-induced heart failure, however insulin resistance explains only a small percentage of these effects [
2,
3]. Importantly, beyond adiposity indexes and insulin resistance, circulating concentrations of resistin (the adipocytokine expressed primarily in monocytes and macrophages, and which responds to inflammatory stimuli) [
4‐
6] predict the progression to heart failure and its prognosis [
7‐
12]. Thus, resistin may in-part explain independent relations between obesity and heart failure and circulating concentrations of resistin may act as potential biomarker for the development of heart failure in obesity. However, there is uncertainty as to the explanation that may account for the ability of circulating resistin concentrations to predict cardiac changes.
Recently, we reported the presence of strong, independent relations between circulating resistin concentrations and left ventricular mass (LVM) in a large community-based sample [
13]. As LVM is a well-recognized determinant of the progression to heart failure, the impact of resistin may in-part be explained by effects on LVM. Relationships between resistin and LVM may nevertheless be accounted for by several mechanisms. In this regard, effects on LVM may be through direct actions on the myocardium as cardiomyocyte overexpression of resistin promotes myocardial hypertrophy in mice [
14‐
17]. However, resistin may also mediate increases in LVM through indirect actions. Indeed, resistin independently associates with decreases in glomerular function [
18] and increases in LVM are strongly associated with renal dysfunction beyond hemodynamic effects [
19]. Alternatively, beyond blood pressure effects, resistin may also enhance afterload to the LV through ventricular-vascular coupling. Ventricular-vascular coupling may account for resistin’s effect on LVM through an enhanced aortic stiffness [
20], as aortic stiffness associates with LVM beyond central arterial blood pressure [
21]. As it is uncertain whether associations between circulating resistin concentrations and adverse cardiac effects may be accounted for by indirect (renal dysfunction or ventricular-vascular coupling) or direct effects, in the present study we assessed the extent to which independent relationships between circulating resistin concentrations and LVM in a large community-based sample are explained by an impact of resistin on renal or aortic function. Furthermore, as general inflammation (as indexed by circulating C-reactive protein [CRP]) may in-part explain the relationship between aortic stiffness and LVM (ventricular-vascular coupling) in hypertensive patients with metabolic syndrome [
22], we assessed whether relationships between circulating resistin concentrations and LVM in a large community-based sample are independent of CRP.
Discussion
The main findings of the current study are as follows: In a large, randomly selected, community-based sample, circulating resistin concentrations were independently associated with indexes of structural changes in the LV including LVMI, LVMinapp, and LVH, as well as with both eGFR and aortic stiffness (carotid-femoral PWV). In this regard, consistent with the well recognized impact of ventricular-vascular coupling and renal dysfunction on LVM, both eGFR and PWV were also independently associated with LVM and LVH. However, in multivariate regression, neither eGFR nor aortic PWV could account for independent relationships between circulating resistin concentrations and LVM or LVH. In addition, in multivariate regression analysis neither PWV nor eGFR significantly modified the contribution of resistin to LVMinappr or LVMI.
The mechanisms that may explain the ability of circulating resistin concentrations to predict the progression to heart failure and its prognosis [
7‐
12] are uncertain. Whilst overexpression of resistin mediates several adverse effects on the myocardium in mice [
15,
16], resistin may produce several alternative changes that may mediate increases in LVM through a multitude of indirect mechanisms. In this regard, resistin was originally identified as a molecule with the ability to mediate insulin resistance in mice and insulin resistance in obesity is a well-recognized cause of cardiac hypertrophy and dysfunction. However, the role of resistin in mediating insulin resistance in humans is unclear and as we have previously described [
13] and similarly demonstrated in the present study, resistin is not associated with HOMA-IR. Moreover, HOMA-IR does not explain independent relationships between resistin and LVM [
13]. Thus, an impact of resistin on LVM through direct myocardial effects mediated by inflammatory changes [
4‐
6], requires consideration. Nevertheless, several alternative indirect effects of resistin need to be excluded. In the present study we addressed the possibility that two important effects of resistin (increases in aortic stiffness or renal dysfunction) may explain the adverse cardiac actions of resistin.
Increases in aortic stiffness are strongly associated with LVM [
21,
29] and these relationships are independent of brachial and aortic pulse pressure as well as the aortic wave component that is driven by increases in aortic stiffness (forward wave pressure) [
21]. In this regard, stiffness of the proximal aorta is thought to increase afterload to the left ventricle through ventricular-vascular coupling [
29]. As resistin is independently associated with aortic PWV but neither aortic pulse pressure, nor the forward wave pressure [
20], the possibility that resistin may mediate increases in LVM through ventricular-vascular coupling requires consideration. Importantly, in the present study, as previously described [
20,
21], circulating resistin concentrations were independently associated with aortic PWV and PWV was independently associated with LVM. However, adjustments for PWV failed to influence resistin-LVM relations, and in multivariate regression analysis PWV failed to modify the contribution of resistin to LVM
inappr or LVMI. Thus, together with the fact that resistin concentrations are not independently associated with brachial, central aortic or ambulatory BP [
20], independent relations between resistin concentrations and LVM are unlikely to be accounted for by load-dependent effects, including an effect of resistin on aortic stiffness. Modifying afterload to the left ventricle is thus not a therapeutic option in preventing the adverse effects of resistin on the heart.
Through renal dysfunction, well before the onset of renal failure, reductions in estimated glomerular filtration rate are strongly associated with LVM and these effects are not attributed to an impact of hemodynamic factors [
19]. As resistin is a well-recognized determinant of renal damage [
18], and in the present study was independently associated with a decrease in eGFR, the possibility that resistin mediates increases in LVM through effects on renal function was considered. Importantly however, although eGFR was indeed strongly and independently associated with LVM, adjustments for eGFR did not modify resistin-LVM relations. In addition, in multivariate regression analysis eGFR failed to modify the contribution of resistin to LVM
inappr and only had a marginal impact on the contribution of resistin to LVMI. Thus, in risk-prediction, the assessment of eGFR, a simple and cost-effective assessment of cardiovascular risk, will not adequately identify the adverse effects of resistin on the LV.
Resistin is induced in response to various pro-inflammatory stimuli such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β [
4‐
6]. Furthermore, resistin has been shown to up-regulate the expression of pro-inflammatory cytokines TNF-α, IL-6, IL-12, and monocyte chemoattractant protein-1 in macrophages. This raises the question of whether the independent relationships between resistin and LVM can be attributed to general inflammatory effects. In this regard however, whilst resistin is independently associated with LVM, the general inflammatory molecule C-reactive protein is not [
13]. Furthermore, although circulating concentrations of TNF-α, and IL-6 independently associate with concentric LV remodeling, there is no relationship between these molecules and LVM [
30]. Although C-reactive protein may in-part explain ventricular-vascular coupling [
22], the relationships between resistin and LVM in the present study were independent of C-reactive protein. Hence, it is unlikely that the resistin-LVM relationships can be explained by general inflammatory effects. Whether resistin has local effects on macrophage function in the myocardium is nevertheless possible. Importantly however, these effects are clearly indexed by circulating resistin concentrations, thus supporting the view that circulating resistin concentrations may be employed as a biomarker of the progression to heart failure.
The relationships between circulating resistin concentrations and LVM beyond indices of obesity (BMI or waist circumference) despite the high proportion of participants with obesity in the current study, suggest that the adverse effects of resistin on LVM are through effects beyond adipose tissue. However, unlike mice, resistin in humans is often undetectable in adipocytes, and the major source of circulating resistin is likely to be peripheral blood mononuclear cells [
6]. Indeed, obese individuals, who are likely to have a greater infiltration of macrophages in adipose tissue, show increased expression of resistin in adipose tissue samples and higher circulating concentrations of resistin than lean individuals [
31]. Importantly, the lack of independent relationships between adiposity indexes and circulating resistin concentrations in the present study are not attributed to inaccuracies in measures of excess adiposity as expected relationships between adiposity indexes and LVM were noted. Consequently, although the impacts of resistin on LVM described in the current study are indeed independent of indexes of either general (BMI) or central (abdominal, waist circumference) obesity, it is possible that the circulating resistin concentrations may in some way be associated with alterations in adipose tissue. The exact adipose tissue changes responsible for the resistin effects on LVM however require further study.
There are several limitations to the current study that require consideration. In this regard, the present study was cross-sectional in design and hence no conclusions regarding causality can be drawn. However, as previously emphasized [
13], the present results are supported by extensive preclinical findings suggesting a myocardial hypertrophic effect of resistin [
14‐
17]. Second, the present study was conducted in one ethnic group in a specific community selected because of the high prevalence of obesity, and the limited confounding effects of antihypertensives on LVM [
13]. Hence, whether resistin-LVM relationships are consistent across populations, is uncertain.
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