Editorial [ The Metabolic Syndrome: Revisiting the Concept, the Diagnosis and the Treatment (Part-II) Guest Editors: John H. McNeill and Vijay Sharma ]

The interrelationships of the Metabolic Syndrome (MetS) are very complex. The list of factors, pathways and systems which appear to be involved is intimidatingly long. How far have we come in our quest to understand the MetS and what is the future direction of this research? In this special issue, we take a comprehensive look at how the concept of the MetS has shaped our understanding of hypertension in a series of reviews. In Part One of our review series, we review the history of hypertension and the MetS, introduce the main concepts and provide a brief overview of the experimental models which are available. In Part Two, we provide a comprehensive overview of the gene-environment interaction with a strong focus on clinical and epidemiological studies. In Part Three, we examine the regulation and dysregulation of blood volume and vascular tone, the two critical determinants of blood pressure. In Part Four, we take a systemic perspective, examining the important roles played by the neuroendocrine and immune systems. We also discuss the concepts of causality and temperospatial organisation as they relate to this research. Finally, we discuss strategies for integrating our vast array of data. Zeidan and Karmazyn then provide a focus on leptin signalling in vascular smooth muscle and its relevance to a wider range of vascular diseases. There is still a great deal of work to be done if we are to fully understand the MetS. To this end, we identified several concepts and approaches which require much more focus and which are seldom addressed directly. The first is peripheral vascular resistance. As we discuss in detail in Part Two of our review series, peripheral vascular resistance is a much more heterogeneous and elusive entity than is generally realised. It is very difficult to establish whether an artery is a true resistance artery in the conscious organism. Furthermore, the arteries which determine peripheral vascular resistance in the resting state may not be the same arteries which respond to changes in blood supply demand. Indeed, there is evidence to suggest that the pattern of vasoconstriction or vasodilation which occurs depends on the provoking stimulus. How such-stimulus specific effects are coordinated is poorly understood. Furthermore, the mechanisms which regulate vascular tone in a particular vessel depend on its location (e.g. cerebral, mesenteric, pulmonary) and size. We do not yet have an integrated understanding of the mechanisms by which peripheral vascular resistance is generated and sustained. This should be an important goal for future research, as it will better inform our efforts to reduce peripheral vascular resistance. The central nervous system neural network that links appetite control stimuli (e.g. leptin, ghrelin, insulin) to blood pressure control networks also requires much further study. A wide range of hormones have been shown to activate the sympathetic nervous system centrally and increase blood pressure. These effects frequently counteract and override the peripheral effects of the same hormones. Central activation of both the sympathetic nervous system and hypothalamo-pituitary-adrenal (HPA) axis has been invoked in a number of models of how the MetS occurs. It is therefore vital that we identify and map out the neural networks which mediate these effects. Our review of the literature highlights the enormous range of MetS-related factors which the reductionist approach has identified. The reductionist approach has been and continues to be a valuable one. However, it is important that we begin the long, painstaking task of integrating the data we have gathered. Computer simulations provide a valuable adjunct tool for this task. These are not meant to replace ‘real’ experiments (a commonly held misconception). They are meant to provoke new thoughts, to help us factor in more variables than can be handled by a conventional experiment (or our own minds), and, as representations of the real system, they are meant to fail; valuable information is gleaned from how computer simulations fail. It is highly unlikely that integration, particularly of data pertaining to a phenomenon as complex as the MetS, will succeed without the use of computer simulations. Finally, we feel that it is important to address the concept of cause and effect, and our methods for establishing cause-effect relationships. Establishing cause and effect relationships within the MetS in humans has proved to be exceptionally challenging. Most of the data pertaining to the interrelationships of the MetS is observational. Furthermore, as experimental studies continue to reveal bidirectional cause-and-effect relationships between factors, we have been forced to gather observational data on the experimental models. It is therefore important that we develop analytical tools that can be used to identify cause and effect relationships in observational data....