Hypertension and dyslipidaemia in obesity and insulin resistance: Pathophysiology, impact on atherosclerotic disease and pharmacotherapy
Introduction
Hypertension, a major risk factor for cardiovascular disease (CVD) (Rosamond et al., 2007), rarely occurs in the absence of other metabolic disturbances (Rudnichi et al., 1998, Kannel, 2000b). Dyslipidaemia is one of the earliest and most frequent metabolic disturbances in hypertensive individuals, occurring concomitantly in over one-third of patients with hypertension (Wong et al., 2006, Thomas et al., 2001). Indeed, dyslipidaemia constituted a powerful independent predictor of myocardial infarction in patients from 52 countries in the INTERHEART study (Yusuf et al., 2004), and the coexistence of hypertension and dyslipidaemia may act additively to increase CVD risk (Neaton & Wentworth, 1992, Thomas et al., 2002) (Fig. 1).
Importantly, hypertension and dyslipidaemia are frequently comorbid in patients with insulin resistance, thereby suggesting that insulin resistance itself may represent a central pathophysiological mechanism underlying their coexistence (Semenkovich, 2006). When high blood pressure, dyslipidaemia and insulin resistance present together, and are in turn associated with hyperglycaemia and visceral obesity, they are collectively identified as the metabolic syndrome. Indeed, this syndrome is characterised by a risk factor constellation that predisposes patients to the accelerated development of atherosclerosis and CVD (National Cholesterol Education Program Adult Treatment Panel III, 2001, Grundy et al., 2004, Gami et al., 2007) (Table 1). Guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) define the metabolic syndrome on the basis of a combination of 3 or more key criteria among a series of 5 (National Cholesterol Education Program Adult Treatment Panel III, 2001, Grundy et al., 2004), whereas criteria recently proposed by the International Diabetes Federation (IDF) (Alberti et al., 2006, International Diabetes Federation, 2006) focus on visceral obesity as a central feature of this condition, with the presence of 2 or more additional criteria (Table 1). Clearly then, the etiology of this disorder remains complex, and a consensus definition based on new insights into the key pathophysiological mechanisms which underlie expression of the metabolic syndrome phenotype(s) should ultimately emerge (Gami et al., 2007).
Dyslipidaemia is a broad term which implies imbalance between elevated circulating levels of cholesterol in the form of apolipoprotein (apo)-B-containing, proatherogenic lipoproteins (including very low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]), and subnormal levels of cholesterol transported in the form of anti-atherogenic high-density lipoproteins (HDL) (National Cholesterol Education Program Adult Treatment Panel III, 2001, Grundy, 2006b, Gazi et al., 2007). It is noteworthy that apolipoprotein levels may be used as informative biomarkers for the numbers of circulating lipoprotein particles. Thus, a single copy of apo-B is present in each atherogenic lipoprotein (including VLDL, VLDL remnants, IDL and LDL), whereas apo-AI is present in essentially all anti-atherogenic HDL particles. It is therefore evident that apo-B and apo-AI levels provide additional quantitative information which complements that of standard lipoprotein-cholesterol measurements such as LDL-cholesterol and HDL-cholesterol. Interestingly, in the INTERHEART study, ratios of apo-B to apo-AI of 4:1 or more were shown to be powerful predictors of the first myocardial infarction in patients across 52 countries (Yusuf et al., 2004).
Use of the apo-B:apo-AI ratio may be of special interest in certain lipid phenotypes, and especially those in which the LDL fraction is dominated by small, dense LDL. Indeed, such particles are poor in cholesterol as compared with large, buoyant LDL particles and may be underestimated by LDL-cholesterol analysis (Sniderman et al., 2006). This is especially relevant to patients with insulin resistance and/or the metabolic syndrome, who often exhibit normal levels of LDL-cholesterol but who present elevated concentrations of dense LDL, in addition to increased levels of VLDL (Guerin et al., 2001, National Cholesterol Education Program Adult Treatment Panel III, 2001, Gazi et al., 2006, Grundy, 2006b). Although LDL remains the most widely used systemic marker of cardiovascular (CV) risk (National Cholesterol Education Program Adult Treatment Panel III, 2001, Grundy et al., 2004), the importance of targeting other lipoproteins to reduce residual CV risk, particularly in patients with the metabolic syndrome, is now under consideration. Indeed, in insulin-resistant states, it is not only the subnormal levels of HDL-cholesterol, but also the defective atheroprotective activities of these particles, which are of special note as potential targets for therapeutic intervention (National Cholesterol Education Program Adult Treatment Panel III, 2001, Choi et al., 2006, Grundy, 2006b, Kontush & Chapman, 2006, Gazi et al., 2007).
Atherosclerosis, the underlying cause of a wide spectrum of CVD outcomes, involves a complex pathologic process thought to be initiated principally at sites of endothelial dysfunction, by the retention, accumulation, and oxidative modification of lipoproteins in the arterial wall (Williams & Tabas, 1995, Chapman, 2007). This process is enhanced in hypercholesterolaemic patients as penetration and retention of LDL in the arterial intima is increased, thus providing higher levels of substrate available for generation of oxidatively-modified, proinflammatory LDL (Steinberg, 2005). The first stage in atherogenesis involves the formation of fatty streak lesions in the arterial intima. Such initial lesions are composed predominantly of cholesterol-rich, monocyte-derived, macrophage foam cells, which typically result from the avid uptake of modified forms of cholesterol-rich LDL, but may similarly be driven by uptake of native VLDL (Milosavljevic et al., 2001). These cells exhibit a proinflammatory, prothrombogenic phenotype (Hansson, 2005). The lesion evolves as further inflammatory and immune cells are recruited from the circulation, with concomitant migration of smooth muscle cells from the outer layers of the arterial wall; such cells may equally take up native and/or modified lipoproteins (including VLDL and LDL) with transformation to foam cells (Hansson, 2005). As the lesion progresses, cytotoxic factors such as oxysterols can induce apoptotic, necrotic or autophagic cell death in inflammatory and immune cells, thereby stimulating the release of both intracellular content and microvesicles. Consequently, intermediate lesions typically progress towards an advanced plaque comprising a necrotic core of cellular debris together with lipoprotein-derived lipids beneath a fibrous cap. Thin, inflammatory fibrous caps are prone to rupture under mechanical stress; rupture may equally be potentiated by intraplaque haemorrhage. Plaque fissure constitutes a key trigger of thrombosis as plaque contents, and notably monocyte-macrophage-derived microparticles containing tissue factor (Mackman et al., 2007), are exposed to circulating procoagulant factors. Consequently, the clinical complications of CVD ensue (Lusis, 2000, Hansson, 2005, Chapman, 2007).
It is now recognised that a major factor in driving atherogenesis is an enhanced immuno-inflammatory response in the vascular wall, for which minimally, moderately or extensively oxidised LDL may act as the initial stimulus (Lusis, 2000, Hansson, 2005). Such an inflammatory response, which intimately involves oxidative stress and perturbation of lipid and cholesterol metabolism, contributes to, but is also a consequence of, endothelial dysfunction (Bonetti et al., 2003, Davignon et al., 2004, Chapman, 2007). Endothelial dysfunction itself features enhanced permeability of the endothelial cell layer and reduced bioavailability of nitric oxide (NO) in the vascular wall, and represents an early marker of atherosclerosis. Moreover, the major CV risk factors, including hypertension, dyslipidaemia, diabetes and smoking, mutually interact at the endothelial surface to exert vasculotoxic effects, which may act synergistically to induce endothelial dysfunction (Bonetti et al., 2003, Frostegård et al., 2003, Davignon et al., 2004) (Fig. 2).
Importantly, elevated levels of oxidised LDL have been documented in individuals presenting with mild to moderate hypertension (Toikka et al., 2000, Frostegård et al., 2003). Moreover, hypertensive individuals have been reported to present a proatherogenic, dense LDL phenotype (Kannel, 2000b, Kazumi et al., 2002). Consistent with these observations, patients with elevated blood pressure display accelerated atherosclerosis as compared with individuals exhibiting “normal” levels of blood pressure; in addition, antihypertensive agents have been shown to slow plaque progression (Toikka et al., 2000, Nissen et al., 2004, Sipahi et al., 2006).
The development of optimal therapeutic interventions that target hypertension and dyslipidaemia for the prevention of CVD requires consideration not only of the underlying pathophysiological mechanisms, and the interactions between these risk factors, but also of the clinical context and potential influence of other metabolic factors on atherosclerotic disease. With rising levels of obesity worldwide (Tzotzas & Krassas, 2004, Baskin et al., 2005), and associated increases in the risk of insulin resistance and type 2 diabetes (Chan et al., 1994, Colditz et al., 1995, Okosun et al., 2001), it is of critical importance to consider their potentially deleterious impact on associated CV risk factors such as hypertension and dyslipidaemia.
This review will therefore cover 2 major areas: 1) Interactions of hypertension and dyslipidaemia in the context of obesity/insulin resistance and metabolic disease; and 2) Mechanisms by which hypertension and dyslipidaemia may interact to exacerbate atherosclerosis and CVD. The clinical implications of these mechanisms for the integrated therapeutic management of CV risk factors in the prevention of CVD will also be evaluated.
Section snippets
Hypertension and dyslipidaemia in obesity and insulin-resistant states
Insulin resistance is considered a critical factor in the development of type 2 diabetes. Equally, insulin resistance, as well as hyperinsulinaemia and hyperglycaemia secondary to insulin resistance, are key elements in driving the expression of a phenotype which typically involves both atherogenic dyslipidaemia and hypertension (Semenkovich, 2006) (Fig. 3).
As previously mentioned, insulin resistance is not typically associated with an elevation in LDL-cholesterol levels, but rather with a
Interaction between hypertension and dyslipidaemia in atherosclerosis
In addition to mechanisms that are operative in obesity and insulin-resistant states, and which may lead to the concomitant development of hypertension and dyslipidaemia, coexistence of these conditions may also arise as a result of the direct hypertensive effects of dyslipidaemia. Indeed, a number of studies have revealed that disorders of lipid metabolism may be associated with exaggerated elevations in blood pressure during exercise or mental stress (Kavey et al., 1997, Sung et al., 1997,
Clinical and pharmacotherapeutic implications
The complex and potentially synergistic interactions that occur between hypertension and dyslipidaemia, on the one hand, and between these conditions and the metabolic factors associated with obesity and insulin resistance on the other, may not only account for the high prevalence with which these conditions coexist, but may also contribute to the high-risk with which they are associated (Wilson et al., 1999, Kannel, 2000a, Haffner & Taegtmeyer, 2003). Given such interactions, the optimal
Therapeutic perspectives to optimise clinical benefit
In summary, the extensive mechanistic interactions between hypertension and dyslipidaemia documented above are consistent with the observation that these conditions are frequently comorbid. Furthermore, mechanisms leading to dysregulation of blood pressure and lipid metabolism are intimately associated with obesity and insulin resistance. However, the molecular and cellular mechanisms which are implicated in the dynamic and potentially synergistic interactions between these CV risk factors, and
Acknowledgments
Excellent editorial assistance was provided by Dr. Elizabeth Harvey of Envision Pharma and funded by Pfizer Inc. Studies performed in the Dyslipidaemia and Atherosclerosis Research Unit (MJC) were supported by INSERM.
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