Utility of Obesity and Metabolic Dyslipidemia (a Non-Insulin based determinate of the Metabolic Syndrome and Insulin Resistance) in Predicting Arterial Stiffness

Abstract

Increased arterial stiffening is not only a hallmark of the aging process but the consequence of many metabolic abnormalities such as IR, obesity, and metabolic dyslipidemia. In patients with the cardiometabolic syndrome, arterial stiffening is consistently observed across all age groups. A core feature linking obesity and the metabolic syndrome to arterial stiffness has been IR. However, including other metabolic abnormalities such as metabolic dyslipidemia increases the risk prediction of arterial stiffness in a dose-dependent fashion. Chronic hyperinsulinemia also increases the activity of both the systemic and the local RAAS which contributes to development of arterial stiffness. All of these relevant metabolic features that predict arterial stiffness are appropriately incorporated in the METS-IR used in the current study.

Obesity, insulin resistance (IR), hypertension, and metabolic dyslipidemia are components of the metabolic or cardiorenal metabolic syndrome which, in turn, predisposes to the development of cardiovascular (CVD) and chronic kidney disease (CKD).¹ In this regard, it is increasingly recognized that arterial stiffness often accompanies the presence of systemic and CV IR and other components of the metabolic syndrome and it is an independent risk factor for the development of CVD and CKD^2,–4. As gold standard determinants of IR such as euglycemic clamps are laborious, lipid parameters and indices of obesity (ie METS-IR) are increasingly being used to predict the cardiovascular risk related to the metabolic syndrome (Bello-Chavolla et al).^5–7 Several potential mechanisms may explain the link between lipid markers of atherosclerosis and arterial stiffness. Plasma TG and HDL-C concentrations are related to insulin-mediated glucose disposal and many studies suggest that the TG/HDL-C ratio provides a simple way to identify individuals who are IR and are at increased cardiometabolic risk. TG/HDL-C is also regarded as a strong indicator of increased small dense low-density lipoprotein particles which, compared with larger low- density lipoprotein particles, exhibit a greater negative impact on endothelial stiffness and function and arterial distensability^5–10.

In the current study, the investigators report use of the METS-IR in a population at risk for CVD correlates with arterial stiffness and is a predictor of incident hypertension.¹¹ The inclusion of BMI as a surrogate for visceral adiposity in the METS-IR, is relevant as recent data support a strong link between adipose tissue remodeling of both visceral fat as well as perivascular fat in the development of vascular IR and stiffness (Fig 1).^12–14 In this regard, dysfunctional metabolic changes in adipose tissue result in altered secretion of bioactive molecules and inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin 6 (IL-6), angiotensinogen, aldosterone, leptin, resistin, and monocyte chemoattractant protein-1 (MCP-1). Elevated circulating levels of adipocyte derived inflammatory cytokines promote vascular IR and increase recruitment and activation of pro-inflammatory immune cells to the vasculature, both of which, in turn, contribute to arterial stiffness. Moreover, greater IR and increased lipolytic activity in visceral adipose tissue leads to increases in free fatty acids (FFAs) which may result in endothelial injury thereby promoting endothelial and vascular stiffness. In addition to the role of visceral fat, the importance of perivascular adipose tissue (PVAT) in vascular biology is increasingly recognized. PVAT not only serves as structural support for most arteries but also secretes molecules with paracrine effects on the vasculature.¹² Hyperplasia of PVAT and infiltration of pro-inflammatory immune cells in PVAT has been demonstrated in obesity and IR.¹³ Maladaptive responses of PVAT also contribute to low grade inflammation, decreased insulin sensitivity, impaired endothelial function and vascular stiffness.¹⁴ Dysfunctional PVAT promotes vascular stiffness though the secretion of several vasoactive factors including aldosterone as well as inappropriate activation of vascular renin-angiotensin-aldosterone system (RAAS). Decreased levels of adiponectin in PVAT also contribute to promotion of vascular stiffness and impaired nitric oxide-mediated vascular relaxation.¹⁵

Fig. 1.

Utility of Obesity and Metabolic Dyslipidemia (a Non-Insulin based determinate of the Metabolic Syndrome and Insulin Resistance) in Predicting Arterial Stiffness.

The presence of aortic stiffening leads to three important abnormalities; 1) the reduction in the capacity to buffer the cyclic changes in blood pressure resulting in impaired arterio-ventricle coupling and diastolic dysfunction, 2) altered structural remodeling of the vasculature characterized by collagen crosslinking and elastin fragmentation leading to systolic hypertension, increased left ventricular workload and reduced myocardial perfusion, 3) the presence of aortic stiffening resulting in prorogation of an excessive pulsatile (kinetic) energy into peripheral organs, such as the kidney and brain, where there is high flow but low pre-capillary resistance or impedance. This persistent excess pulsatile wave to the end organ, referred to as pulsatility, damages capillaries and thus tissues in these high flow organs and establishes the cardiovascular risk associated with the cardiometabolic syndrome.^16,17

Various metabolic risk factors and vascular biologic processes promote arterial stiffness. Measurements of arterial stiffness may therefore not only provide information about prevalent processes but also insight regarding the cumulative history of metabolic risk factor exposure.18,19 However, the mechanisms that underlie the role of metabolic abnormalities and development and arterial stiffness is not well understood. To this point, arterial stiffness is related to development of endothelial and vascular smooth muscle stiffness as well as maladaptive extracellular matrix alterations including collagen accumulation, elastin degradation and cross-linking of the extracellular matrix.^{4, 20,21} Recent studies support a critical role for endothelial stiffness and impaired endothelial nitric oxide (NO) production in development of whole arterial stiffness.²² In this regard, metabolic dyslipidemia may contribute to vascular endothelial IR, endothelial stiffness and impaired NO production which leads to stiffening of other components of the vasculature.^4,23 IR states and the resultant endothelial stiffness are also characterized by an imbalance between endothelial production of important opposing regulators of arterial stiffness, such as NO and endothelin-1, whose levels are reduced and increased, respectively.^{23, 24} Endothelial and whole vessel stiffness is also promoted by activation of the systemic and local renin-angiotensin-aldosterone axis as well as vascular mineralocorticoid receptor activation and increased expression of angiotensin II type 1 receptors leading to vessel wall hypertrophy and fibrosis, which reduce arterial elasticity.^{24, 25}