| COMMENTARIES |
Teasing Out and Rebuilding the Metabolic Syndrome: Hypertension and Dyslipidemia in Obesity and Insulin Resistance, Atherosclerotic Disease, and Pharmacotherapy
Keith Suckling, 291 Knightsfield, Welwyn Garden City, Hertfordshire AL8 7NH, U.K, Email: keith@suckling291.freeserve.co.uk
The detailed investigations which most of us plan and carry out require an overall framework (or paradigm or narrative) for their construction, understanding, and communication. For atherosclerotic disease over the past several decades these have been based on concepts focused on cholesterol, then in more detail on LDL cholesterol and oxidized LDL, to which was added inflammatory mechanisms and the pathology of the vulnerable plaque. Clearly these offer many areas of detailed biology to investigate in themselves, but in the past decade or so the concept of the metabolic syndrome has provided a linking of even more metabolic and physiological processes so offering an even richer and more complex landscape to explore.
The importance of the metabolic syndrome as a driver for novel research cannot be overestimated despite the continuing debate mainly in clinical circles about the value of the metabolic syndrome in practice, for example in identifying patients at risk and then determining the most appropriate treatment. Recent reports show that the debate continues. Sattar and colleagues argue from data in the PROSPER trial that simpler tests than the metabolic syndrome are better for cardiovascular disease risk prediction [1]. Another recent study makes similar points [2]. These are examples of the use of the metabolic syndrome concept in a specific area of clinical practice, but many would want to argue that it is more than that, that it provides a framework for linking aspects of pathology that are reaching epidemic proportions [3].
Whatever the attitudes to the value of the metabolic syndrome in clinical practice may be, the now well-accepted relationships between its main components require mechanistic explanation. We do not know whether there is an underlying single cause, which would then be a prime target for a single hit therapy, or whether the links between the molecular and physiological processes are so elaborate that when one part of the network begins to move away from optimum, others are then affected, no doubt to differing degrees according to the tightness of their association. The therapeutic implications of this situation would then be much more complex, but one may hope that a more detailed understanding of the network might identify the points of greatest sensitivity where the greatest impact might be made. Recent examples include the suggestion that secretion of VLDL from the liver is a primary factor in the metabolic syndrome [4] and data to suggest that in adipose tissue in insulin resistance T-lymphocyte infiltration is a primary process [5]. Any individual study can only address smaller well-defined fields in the overall landscape (although more consideration might be given to multi-factorial design in preclinical studies) so it is essential at regular intervals to bring data of all kinds together and to attempt a synthesis. In a recent review [6] Chapman and Sposito do just this by focusing on a limited but still broad area of hypertension and dyslipidemia in the context of insulin resistance and obesity.
If we were to lay out the figures in this review across a table we would see a very clear progression of concept and detail which follow the argument that the authors present. As a starting point the associations defined by epidemiology between CHD death rates and total plasma cholesterol and systolic blood pressure offer an unambiguous pattern. The mechanistic analysis begins by listing the players and the stadium in which they interact. Hypertension, dyslipidemia, diabetes/insulin resistance, smoking, and low shear stress are identified as interacting with the vascular endothelium causing a dysfunction characterized by vasoconstriction, oxidative stress, inflammatory cell adhesion and/or filtration, smooth muscle cell proliferation, and endothelial permeability. All these will be recognized as major factors in the development of atherosclerosis and CHD. To take this synthesis of factors further we need to add more molecular and physiological detail. Thus, for example, the fat accumulation in obesity results in increased secretion from adipose tissue of interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α, angiotensin (Ang) II and leptin, and decreased adiponectin. These in turn contribute to insulin resistance and hypertension. This is just part of the network Chapman and Sposito define and analyze in more detail.
Several more detailed mechanisms are considered based on published data, and these provide a conceptual framework for a more complete understanding of the network. For example, the elevated circulating levels of endothelin (ET)-1 and Ang II in both hypercholesterolemia and insulin resistance work with enhanced activity of the ET-1 and Ang II receptors to upregulate vascular tone and promote an increase in blood pressure. This is linked to enhanced activity of pro-oxidant enzymes such as NAD(P)H oxidase which increases the production of superoxide anions and favors the inactivation of nitric oxide (NO). A consequence of this is attenuation of the inhibitory effect of NO on ET-1 and Ang II. Mechanisms by which NO availability might be reduced are considered. These include the inactivation of NO by superoxide anions produced by NAD(P)H oxidase, which thus becomes a focus of the events. LDL is also oxidized by the superoxide and the oxidized LDL can reduce the transcription rate of endothelial nitric oxide synthase (eNOS) and the degradation of eNOS mRNA. In addition to these mechanisms circulating levels of the natural analogue of asymmetrical dimethylarginine (ADMA), which are elevated in patients with hypercholesterolemia or insulin resistance, may act as a competitive inhibitor of eNOS. Relevant to these processes, endothelial arginase II has recently been proposed as a novel target for therapy in atherosclerosis [7] and very recent data also support ADMA as a target [8].
At a more physiological level mechanisms acting though baroreceptors and the sympathetic nervous system are described. In insulin resistant states, obesity and hypercholesterolemia baroreceptor sensitivity is decreased. This means that elevations in blood pressure are not effectively modulated by the reflex and it leads to sympathetic activation and consequent hypertension. Similarly hypercholesterolemia and insulin resistant states show an impaired response in plasma volume expansion and increase in cardiac output following dietary salt intake due to impaired endothelial function in the microcirculation. These effects may be relevant to the fluid retention observed with the insulin-sensitizing drugs, the glitazones. Interestingly, returning to a topic that was first studied in the 1970s: they suggest that another contributor in hypercholesterolemia might be cholesterol enrichment of the plasma membrane of vascular smooth muscle cells. This could stimulate the activity of the L-type voltage-sensitive calcium channel causing an increase in calcium influx and myogenic tone. Finally, they show that in hypertension there may be an increase in the penetration of atherogenic lipoprotein particles through the stressed endothelium. With the mechanisms of lipoprotein oxidation noted above and others in macrophages an increase in the presence of atherogenic modified lipoprotein particles would result. The overall conclusion is that we are looking at a network of mechanisms. None is independent of the others and this clearly impacts how pharmacological therapy is addressed.
This interesting review concludes with an assessment of the complexity of the networks that have been described. An essential cautionary note about over-reliance on animal models [9] and the need for exploratory clinical research is made. Here biomarkers of mechanisms as well as those which may indicate clinical benefit are both important. From a therapeutic perspective, Chapman and Sposito review the many current options noting results from recent trials and current guidelines. To these the somewhat debatable polypill concept, which is reported to be progressing in two approaches, may be added (http://www.worldheart.org/press/press-releases/news-details/article/polypill-reaches-clinical-testing-phase-1/). This is one response to the fact that, as Chapman and Sposito note, physicians currently tend to target CV risk factors in isolation. For novel approaches, their analysis particularly emphasizes the potential for benefit in restoration of endothelial dysfunction which might be done by enhancing NOS activity or local NO concentrations. Very recent data from animal studies suggest that this may be possible [10,11].
In some fields one major review can define the story for many years. Given the complexities of the networks associated with hypertension, dyslipidemia, and atherosclerotic disease we can expect regular updates of the kind presented by Chapman and Sposito to be necessary for many years to come.
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