Thematic Reviews on the Pathogenesis of Atherosclerosis

doi:10.1194/jlr.E400001-JLR200

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Thematic Reviews on the Pathogenesis of Atherosclerosis

Joseph L. Witztum, Editor-in-Chief

This issue inaugurates a new Thematic Series that highlightsone of the important clinical consequences of disturbances inlipid and lipoprotein metabolism, namely atherogenesis. Atherosclerosisand its complications are still the major source of morbidityand mortality in the industrialized world, and estimates havebeen offered that, at its present rate of growth, it will bethe major cause of death from disease by the year 2020 in theentire world. Atherogenesis is a disease that, at its earliestphase, appears to be present even in fetal life, and it evolvesslowly over decades, impacted by a myriad of environmental andgenetic factors. Clearly, hypercholesterolemia is a dominantrisk factor for this disease, and innumerable clinical trialsof various hypolipidemic agents now document the efficacy ofcholesterol-lowering therapy. For many years, some of us haveargued that any LDL cholesterol level above $~$ 50 mg/dl is notideal, and that the risk for cardiovascular disease (CVD) increasesproportionately as values exceed the ideal. Recent clinicaltrials have convincingly shown that lowering LDL cholesterolvalues below 100 mg/dl is desirable, and the ideal target valuesare being explored. Only in the past few months, the PROVE-ITtrial has shown, for the first time in a high-risk population,that a target LDL cholesterol level of $~$ 60 mg/dl is superiorto 90 mg/dl, a target value that until recently had been consideredto be appropriate. In the near future, we can expect furtherclinical trials to fully define the optimal goals for hypolipidemictherapy, both for secondary as well as primary prevention.

However, atherosclerosis is a complex and multifactorial disease,and even if one accepts the "new" dogma that any LDL value above50 mg/dl is potentially atherogenic, it is not likely that thistarget will be achieved in a large percentage of patients, and,more importantly, will not be achieved in the population asa whole. Furthermore, there still remains an enormous degreeof heterogeneity in disease expression among individuals withequivalent LDL values and even equivalent degrees of other knownrisk factors. This is emphasized by the two to three decadedifferences, or more, in expression of CVD that have been observedeven among subjects with Homozygous Familial Hypercholesterolemia,who uniformly have exceedingly high LDL values. Even among populationstreated with effective hypolipidemic agents, such as the statins,there remains a very large residual of disease activity, a pointoften lost sight of. Clearly, the complexities of lipid andlipoprotein metabolism, and the differing responses of vascularwall cells to the interplay of lipoproteins and to the vastarray of circulating cellular and blood elements, are enormous.Those factors that are involved in the initiation of disease,those involved in its progression and in its perpetuation andchronicity, and those that lead to radical changes in morphologythat result in clinical events may in turn each have their ownindependent set of interacting factors. To add to the complexity,there is an enormous contribution of both environmental andgenetic factors that individually and synergistically affectdifferent aspects of the disease process, effecting both protectiveand proatherogenic consequences in the face of LDL values abovethe ideal.

In the current Thematic Series, we will begin to address a fewof the current themes on which a large body of work has beendeveloped to suggest that the particular topic plays an importantrole in the complexity of this disease. Over the ensuing years,we will try to cover many aspects of atherogenesis, with anemphasis on those aspects of lipid and lipoprotein metabolismthat remain the preeminent focus of the Journal of Lipid Research(JLR).

In this initial series, we will explore a group of common themesthat revolve around what might be considered to represent inflammatoryaspects of atherogenesis. The initial paper in this series exploresthe "oxidation hypothesis," one of the most widely studied aspectsof current atherogenesis research, which has made its way intothe clinical arena, although early trial data provided disappointingresults. This review will especially emphasize one of the dominantthemes to emerge from the oxidation hypothesis, namely, therole played by a specific set of oxidized lipid moieties, oxidizedphospholipids, and the role of HDL in this complex story. Asubsequent thematic review will explore in depth the effectsof infection and generalized inflammation on lipid and lipoproteinmetabolism. That paper will provide a uniquely detailed reviewand a comprehensive bibliography of this timely subject. Infuture reviews, we will explore the role of nuclear hormonereceptors on lipid and lipoprotein metabolism and their complexroles on inflammation and atherogenesis. Finally, we will explorehow the use of genetic studies can help sort out the immensecomplexities that mediate these aspects of atherogenesis. Futureseries will focus on the many other biological factors thataffect atherosclerosis, such as the role of immune functionand the emerging evidence of the enormous contribution of adiposetissue to disturbances in lipid metabolism and inflammation.

We will shortly also inaugurate a unique and fascinating insightinto the History of the Cholesterol Hypothesis, as seen fromthe perspective of one of the leaders in the "cholesterol wars,"who has played a pivotal role in bringing to recognition thenow widely accepted notion that the "lower the cholesterol levelthe better." Many of my young colleagues, both in the clinicand in the lab, do not realize and cannot imagine that our currentemphasis on aggressive dietary and therapeutic programs to lowerLDL cholesterol levels was a subject of deep controversy onlya few decades ago. They are unaware of the intense scientificdebate, and even public controversy, that ensued over the questionof whether one should even lower cholesterol levels at all.This debate was marked not only by genuine scientific discoursebut by personal attacks and extremism not commonly associatedwith what should be a scientific issue. Dr. Daniel Steinberghas a unique perspective on this controversy, from his leadershiproles at both the NIH and at the University California, SanDiego, where for decades he has been one of the preeminent internationalscientists involved in both the scientific and public aspectsof this debate. Dr. Steinberg is not only a highly observantreporter, but he can tell a tale as can few others. His lectureshave always been enjoyed not only for their scientific wisdom,but equally for the eloquence and humor of the presentation.He is currently engaged in writing a personal perspective ofthe cholesterol controversy, from its origins to its currentstatus. We are excited and privileged to have the opportunityto present some of this in serial fashion over the next fewyears. After reading the first chapter in this most revealingstory, which will debut in a few issues, we are sure that eachand every issue of the JLR containing one of these chapterswill be eagerly awaited. We think these reviews will not onlybe entertaining, but, of more importance, they will sketch thebirth and development of what is now recognized as one of thedominant scientific accomplishments of modern medicine, withenormous public health importance for the population as a whole.The lessons to be learned are important. A vital idea must befought for and proven, and there will be controversy along theway. It is an important lesson for all of us in the scientificcommunity, especially those of us interested in lipid researchand its clinical applications.

We begin this new series in the current issue with a reviewof the current status of the relatively newly developed "oxidationhypothesis" of atherogenesis, a subject currently under considerabledebate, as well it should be. The lessons to be learned fromthe long gestation of translating the cholesterol hypothesisfrom theory to practice should put into perspective what willbe needed to determine the importance of this idea and othersthat arise.