Background
Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular (CV) morbidity and mortality [
1] and a major pathophysiologic mechanism linking T2DM to CV risk is diabetic dyslipidaemia, characterized by high triglycerides (TG) and low high density lipoprotein cholesterol (HDL) plasma levels [
2]. The two lipids are closely connected in T2DM, since the insulin resistance-induced increase in plasma TG triggers the catabolism of HDL, and consequently, a specific role of the two lipids in CV organ damage is not clearly understood [
3]. Moreover, T2DM is a chronic low-grade inflammation state [
4], and inflammatory cytokines may also influence plasma lipids levels [
5,
6]. Interleukins (ILs) stimulate hepatic secretion of TG [
6] and up-regulate expression and activity of matrix-metalloproteinases (MMPs) [
7], the endopeptidases that decrease HDL levels through degradation of apolipoprotein A-I [
8]. Yet, interleukins and MMPs may not only modify lipid profile but also directly damage CV system [
9‐
13].
It is evident that the relationship between lipids, inflammation and CV organ damage in T2DM patients is complex. Number of studies have shown the associations of TG, HDL, ILs or MMPs with vascular and cardiac alterations [
9,
12‐
17], yet the majority of these studies have evaluated the impact of a single metabolic abnormality on a single CV measure, without taking into consideration the relationships between lipids and inflammation and without considering that the heart and large arteries are closely anatomically and functionally linked and that the changes in vascular tree have impact on the structure and function of the heart.
To understand better the role of dyslipidemia and inflammation in CV organ damage and CV risk of T2DM patients, the present study evaluated the inter-relationships between TG, HDL, ILs and MMP-12, as well as the associations of lipids, ILs and MMP-12 with different measures of CV structure and function, both in T2DM patients and in subjects free of diabetes (nonT2DM).
Discussion
The present cross-sectional study investigated the relationships between plasma lipids and inflammatory cytokines as well as the impact of lipids and ILs on CV system in T2DM patients. Plasma ILs were directly related to plasma levels of MMP-12 that were inversely related to HDL. MMP-12 was independently associated with carotid diameter, arterial stiffness and LV mass, whereas HDL was independently associated with carotid wall thickness and LV diastolic longitudinal performance.
MMP-12 is a potent elastase highly expressed in macrophages [
27]. Diabetes-related metabolic abnormalities, like hyperglycemia, promote macrophage activation and enhances the expression of the inflammatory mediators [
28]. Inflammatory cytokines induce MMPs transcription and activation resulting in extracellular matrix alteration [
7,
17,
29] that, in the case of MMP-12 activation, is a cleavage of elastin. Elastin is the principal stress-bearing element of large arteries and its fragmentation leads to arterial dilation since arteries cannot withstand anymore the outward forces exerted by arterial pressure [
30]. Degradation of elastin contributes also to arterial stiffening. In our T2DM patients, MMP-12 increased with plasma levels of IL-6 and IL-18 and was independently related to elastic artery diameter and stiffness and to LV mass. The association between MMP-12 and LV mass was probably mediated by arterial stiffness as suggested by studies in mice with elastin haploinsufficiency [
31].
The role of MMP-12 in arterial wall enlargement and stiffening has been demonstrated in experimental and clinical studies. In MMP-12 knock-out mice, the growth of aortic diameter and the expression of MMP-12 in aortic wall were significantly lower as compared to wild-type mice [
32], and an experimental injury of femoral artery did not induce increase in arterial stiffness and MMP-12 mRNA activation that were observed in wild-type mice [
33]. In patients with acute dissection of ascending aorta, the plasma levels of MMP-12, IL-6, and IL-8 as well as MMP-12 activity in aortic wall were significantly higher as compared to subjects free of dissection [
34,
35].
It is worth to note, that in nonT2DM subjects were observed the same direct associations between ILs and MMP-12 and between MMP-12 and CV measures as in T2DM patients. However, since the levels of ILs and MMP-12 were significantly lower, MMP-12 was independently related only to carotid diameter. This observation is in agreement with results of the Strong Heart Study showing that cardiac target organ damage precedes clinical appearance of T2DM and is related to inflammatory status [
36].
Some members of the MMP family, including MMP-12, can degrade the apolipoprotein A-I and decrease circulating HDL levels [
8,
37]. In T2DM and nonT2DM populations, plasma MMP-12 was inversely related to plasma HDL levels, which in turn were independently related to mitral longitudinal diastolic velocity e′ in both populations and to mitral longitudinal systolic velocity s′ in nonT2DM subjects. Longitudinal velocities of mitral annulus provide important physiologic information on LV diastolic and systolic performance [
25]. In experimental study on anesthetized dogs, an increase in early diastolic velocity e′ during dobutamine infusion was associated with reduction of τ, consistent with faster relaxation, while the reduction in e′ velocity during ischemia was associated with prolongation of τ, consistent with slower relaxation [
38]. Similarly, systolic s′ velocity increased during dobutamine infusion in dose-dependent manner and was strongly associated with dP/d
tpeak [
39]. A direct association between HDL levels and LV longitudinal systolic and diastolic performance observed in our populations can be explained by studies showing that HDL increases insulin-independent glucose uptake in rat cardiomyocytes via an Akt signaling pathway [
40] and that HDL mimetic peptide improves LV diastolic dysfunction in cholesterol-fed rabbits [
41].
In T2DM patients, HDL was also independently and inversely related to cIMT. This association has been already described in a large meta-analysis including 21.000 subjects [
14] and is probably related to the fact that HDL is able to suppresses smooth muscle cells migration and proliferation [
42].
The combined role of ILs, MMP-12 and HDL in CV organ damage of T2DM patients was confirmed also by our observation that diabetic patients with established organ damage, i.e. with increased carotid IMT, aortic stiffness and LV hypertrophy, had significantly lower plasma levels of HDL and higher levels of ILs and MMP-12 as compared to those without vascular and cardiac impairment.
The only CV measure associated with the presence of CV disease in T2DM patients was cfPWV [
43]. Indeed, increase in aortic stiffness has a wide impact on CV system. First, it reduces a cushioning function of large arteries thus increasing flow pulsatility in sensitive organs like kidney and brain [
44,
45]. Second, it anticipates a return of reflected waves to the heart in late systole, thus augmenting the late-systolic LV wall stress. Increase in LV wall stress stimulates adaptive thickening of myocardial fibers and development of LV hypertrophy [
46,
47] that may negatively influence LV myocardial performance. In our T2DM patients, with increasing cfPWV increased end-systolic LV stress and LV mass, which both were inversely related to LV longitudinal systolic performance [
48]. Interestingly, in nonT2DM subjects, the only CV parameter associated with CV events was LV longitudinal systolic velocity s′, a finding consistent with results of meta-analysis demonstrating that global LV longitudinal strain is an accurate predictor of major adverse cardiac events [
49].
Study limitations
The present study has some potential limitations. First, plasma insulin levels were not measured, and thus the impact of insulin on ILs, MMP-12 and CV biomarkers cannot be evaluated. Second, measuring HDL levels does not accurately depict their composition and functionality, which can be modified in diabetes. Third, LV diastolic performance was evaluated only by early diastolic longitudinal velocity of mitral annulus and no additional echocardiographic parameters related to LV relaxation and compliance were assessed. Finally, we are aware that cross-sectional design of the study cannot clearly elucidate cause-and-effect relationships.
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