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The FDA Critical Path Initiative and Its Influence on New Drug Development∗ Janet Woodcock1 and Raymond Woosley2 1

Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Maryland 20857; email: [email protected]

2

The Critical Path Institute, Tucson, Arizona 85721; email: [email protected]

Annu. Rev. Med. 2008. 59:1–12

Key Words

The Annual Review of Medicine is online at http://med.annualreviews.org

biomarkers, biomarker qualification, clinical trials

This article’s doi: 10.1146/annurev.med.59.090506.155819

Abstract

c 2008 by Annual Reviews. Copyright All rights reserved 0066-4219/08/0218-0001$20.00 ∗ The U.S. Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper.

Societal expectations about drug safety and efficacy are rising while productivity in the pharmaceutical industry is falling. In 2004, the US Food and Drug Administration introduced the Critical Path Initiative with the intent of modernizing drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. An important part of the initiative is the use of public-private partnerships and consortia to accomplish the needed research. This article explicates the reasoning behind the Critical Path Initiative and discusses examples of successful consortia.

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INTRODUCTION


In 2004, the US Food and Drug Administration (FDA) launched the Critical Path Initiative, a project that is intended to improve the drug and medical device development processes, the quality of evidence generated during development, and the outcomes of clinical use of these products. Why would a regulatory agency be involved in such a modernization effort? FDA’s mission is to protect and promote the health of the public. With respect to drugs, biological products, and medical devices, this translates into ensuring reasonable product safety while also facilitating the translation of scientific innovations into commercial products. The ongoing tension between these two objectives results in assertions that FDA requirements are stifling innovation, and simultaneously that FDA standards are too low. The thesis of the Critical Path Initiative is that scientific advances in the development process are the best way to resolve these conflicts to the satisfaction of most parties and to the benefit of the public. Although the initiative concerns all regulated medical products, this review discusses Critical Path in the context of drug development.

BACKGROUND Rising Expectations about Drug Development In 1962, congressional amendments to the Food, Drug, and Cosmetic Act created for the first time a requirement that drugs be scientifically shown to be effective before they could be marketed (a requirement for safety had been in effect since 1938). During the 1960s–1980s, drug developers, the academic community, and regulators worked to develop and refine ways to design, conduct, and analyze randomized controlled clinical trials that could produce the needed evidence. Many important advances in pharmacotherapy (e.g., cardiovascular therapies, psychiatric drugs, anti-infectives, and cancer treatments) 2

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were introduced during this era. However, the evidence generated in drug development programs was still somewhat limited. For example, dose-response information was usually scanty, often few women were studied, data on long-term use (even for chronically administered drugs) were lacking, evaluations of subgroups such as patients with renal or hepatic insufficiency were not conducted, and data on drug-drug interactions were not available. From the mid-1980s through the 1990s, as an increasing number of drug therapies became available, the FDA as well as the international regulatory community established the expectation that such information would be obtained during most drug development programs. Therefore, modern development programs usually are much more extensive and contain many more clinical studies and patient exposures than was usual in 1960–1985. Despite these advances, there remains a great deal of uncertainty about the performance of drugs that are new to the market. Data from long-term use are still usually limited. Current drug development programs cannot detect drug-related adverse outcomes that represent a small increase in frequency of a problem that is already common in the treated population (e.g., ischemic cardiovascular events). Technologies to predict the occurrence of rare, catastrophic side effects are not available. Additionally, despite attempts to make the results of clinical trials more generalizable, the patients enrolled in trials do not reflect the full range of the population or treatment situations that occur in practice. As a result, new safety issues are often identified only after drugs enter the market. Nevertheless, in the past decade, aggressive marketing techniques have led to immediate uptake and widespread use of many new drugs, combined with a general expectation that their performance is well understood over a wide range of clinical situations. In particular, many members of the public believe that if prescription products are advertised on television, they must be safe. The increasing


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recognition of this problem has led to calls for larger trials and longer patient exposures prior to drug marketing. Not only drug development but also medical practice has become increasingly complex since the 1962 amendments. For many diseases, multiple subgroups and disease stages have been defined, and numerous therapeutic options exist. Drug development programs are rarely designed to answer the questions posed by evidence-based medicine and by insurers: What therapeutic option has the best outcomes in various patient groups or, similarly, what option provides the best value? If comparative trials are performed premarket, they usually involve a demonstration of “noninferiority” in comparison with a single control drug. Increasingly, members of the health care community, as well as Congress, are calling for more of this information to be developed.

Problems with the Pharmaceutical Pipeline The pharmaceutical industry is facing a productivity crisis. Despite rising investment in pharmaceutical research and development, successful development of novel drugs is slowing (Figure 1). In fact, 2004 represented a 20-year low in introductions of new chemical entities (NMEs) worldwide (1). The same phenomenon has been observed in the United States, where the submission rate of new drug applications for NMEs has shown a downward trend in the past decade (2). Not surprisingly, the investment needed per successful NME has risen to an estimated $800 million or more (3, 4). This cost is driven by the high rate of clinical failure, estimated at 70%– 90% of candidates (5). The rising percentage of late-stage clinical failures, now ∼50% of compounds tested in phase 3 trials, is of particular concern. The high cost of successful drug development may discourage investment in more innovative, risky approaches, as well as in therapeutics for diseases that represent smaller markets. Additionally, the need

Global R&D spend ($bn)

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Figure 1 Comparison of global pharmaceutical industry research and development investment and global output of new molecular entities. Source: Hoekema A. 2007. Sharing risks and rewards—basis for a turnkey pharma-biotech alliance in osteoarthritis. Drug Disc. World Spring:54

to recoup this investment during the period of market exclusivity, prior to the introduction of generic copies, is an incentive for aggressive marketing techniques (6). However, rapid market uptake means that a large number of individuals may have already been exposed by the time a drug problem is discovered after marketing. Thus, rising societal demands for greater certainty about the outcomes of drug therapy are occurring at a time when the pharmaceutical industry is experiencing difficulty in sustaining innovation. These concurrent trends are a cause for significant concern, given the number of medical conditions that currently have unsatisfactory or no therapeutic options. The FDA, with its dual roles of protecting and promoting health, is charged with implementing policies that ensure that the benefits of new products will outweigh their risks, while simultaneously promoting innovations that can improve health. The challenges inherent to this mission drove the genesis of the Critical Path Initiative. www.annualreviews.org • The FDA Critical Path Initiative

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Expectations have been widespread that 30 years of significant public investment in biomedical research would produce an explosion of new therapies for previously untreatable or inadequately treated diseases. The failure of this surge to materialize has prompted extensive speculation on the cause of this “pipeline problem.” Many in the drug development community believe that genomics and other newer technologies are not yet sufficiently mature to reliably support drug development. Others blame industry business decisions or regulatory requirements. In 2004, the FDA published a White Paper entitled “Innovation or Stagnation: Challenges and Opportunities on the Critical Path to Medical Product Development” (7). While acknowledging that a combination of factors has likely led to the current drug development situation, this paper called attention to an important and

generally unrecognized problem: the lagging science of drug development. Drug development can be conceptualized as a process leading from basic research through a series of developmental steps to a commercial product (Figure 2). The FDA White Paper identified the “Critical Path” as a process beginning with identification of a drug candidate and culminating in marketing approval. Along the path to marketing, the product is subjected to a series of evaluations to predict its safety and effectiveness and to enable its mass production. Despite extensive investment in basic biomedical science over the past three decades, there has been very little change in the science of the development process. The sophisticated scientific tools used in drug discovery and lead optimization are generally not utilized in the preclinical and clinical development stages. Instead, traditional empirical evaluation is used in both animal and human testing. We are

Working in Three Dimensions along the Critical Path Prototype Design or Discovery

Preclinical Development

Clinical Development

Material Selection Structure Activity Relationship

In Vitro and Animal Testing

Human and Animal Testing

In Vitro and Computer Model Evaluation

In Vitro and Animal Models

Human Efficacy Evaluation

Physical Design

Characterization Small-Scale Production

Manufacturing Scale-up Refined Specifications

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Safety

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FDA’S CRITICAL PATH INITIATIVE

Medical Utility

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FDA Filing/ Approval & Launch Preparation Safety Follow Up

Mass Production

Figure 2 The critical path of drug development. First, a candidate drug emerges from a drug discovery program. The candidate must successfully complete a series of evaluations of its potential safety and efficacy and must be amenable to mass production. For each candidate finishing the pathway, 5000–10,000 are evaluated in the discovery phase. 4

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using the tools of the last century to evaluate this century’s advances. How did this situation come about? The FDA’s analysis, which has been generally accepted, is that “no one is charged” with improving developmental science. The National Institutes of Health (NIH) focus on innovative biomedical science, not the applied science of the development process; as a result, academia also concentrates on basic science. The pharmaceutical industry is concerned with developing innovative products. The FDA, as a regulator, is not charged with— nor is it funded for—improving the process, although it has been involved in such efforts. Additionally, the science needed is generally integrative “big science” that requires contributions from multiple disciplines and sectors and is not within the purview of a single investigator or firm. How is the evaluative science of development related to “translational science”? Translational science, which is also called “experimental medicine,” or simply “clinical pharmacology” in the case of drug development, involves moving a scientific innovation from the laboratory into early clinical studies (8). Improvement in this part of the process is an essential step in modernizing drug development.

THE CRITICAL PATH PROGRAM FDA’s 2004 Critical Path White Paper generated considerable discussion and debate among drug and device developers, academics, and patient advocacy groups. Over 100 groups submitted comments on the paper. After extensive consultation with numerous stakeholders, FDA issued the “Critical Path Report and List” in 2006 (9). This report enumerated leading areas for scientific improvement in the development process: development and utilization of biomarkers; modernizing clinical trial methodologies and processes; the aggressive use of bioinformatics, including disease modeling and trial simulation; and improvement in manufactur-

ing technologies. It also contained the “2006 Critical Path Opportunities List,” 76 discrete projects that, if completed, could improve product development and subsequent use. A number of these projects are now being undertaken, many in partnership with FDA (10).

Development and Qualification of New Biomarkers Development of new biomarkers was identified as the highest priority for scientific effort. Genomic, proteomic, and metabolomic technologies, as well as advanced imaging techniques, hold tremendous promise for generating new biomarkers that can reflect the state of health or disease at the molecular level (11). Although much prior discussion about the use of biomarkers in drug development has focused on surrogate endpoints for effectiveness, most uses of new biomarkers are not expected to involve surrogacy. For example, prediction of adequate safety is an essential part of drug development. Currently, preclinical safety testing involves traditional animal toxicology studies, as well as in vitro assays such as the Ames test. Animal toxicology tests are very useful for assessing safety for initial human testing; however, they often fail to uncover the types of toxicities seen after widespread human exposure. New technologies, such as gene expression assays in whole cell or animal systems, proteomics, or metabolomics, may provide much greater insight into the whole spectrum of pharmacologic effects of a candidate drug. Such technologies may also be useful in comparing the candidate’s effects (particularly off-target effects) to those of other drugs in its class or other drugs intended for similar uses (12). Drug developers are just beginning to use such technologies in the preclinical safety workup, and the clinical implications of such findings have not been worked out. The current scheme for clinical safety testing has also failed to incorporate recent scientific advances. Human safety during drug development is primarily evaluated on an www.annualreviews.org • The FDA Critical Path Initiative

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observational basis from subjects exposed in the various developmental trials. The markers used to assess potential human toxicity are also assays that have been available for decades, e.g., clinical chemistries and hemograms. Few explanatory studies are carried out to determine the mechanism of an observed side effect, and assays to predict rare side effects are not available. Despite premarket exposure of thousands of subjects, serious side effects are frequently uncovered after marketing. New types of biomarkers may provide opportunities for prevention or early detection of these adverse events. The current problems with predicting and evaluating drug efficacy could also be ameliorated by using biomarkers. Many drug efficacy problems stem from the extreme variability of human disease response. New biomarkers can improve diagnosis, define disease subsets that may differ in response, define individual variability in the drug’s molecular target, and provide an early readout of response to therapy (11). For example, both in vitro diagnostics and imaging techniques are expected to provide additional information about disease subsets. This is already beginning to happen in cancer, where gene expression assays are being used to supplement histologic and clinical assessments of tumors, e.g., evaluating the likelihood of recurrence and the need for adjuvant therapy. For disorders such as psychiatric conditions that are currently diagnosed by clinical symptoms, it is hoped that genetic or imaging markers may help to distinguish biologically based subsets. A related type of biomarker is one used to predict treatment responsiveness. Many new cancer therapies target a specific molecule or cellular pathway. Genetic, proteomic, or other molecular assays that assess target status within a tumor may be used to predict responsiveness to a targeted drug. This is the strategy used with the drugs trastuzumab (Herceptin®) and imatinib (Gleevec®). Interindividual drug target heterogeneity due to genetic polymorphisms may be important in diseases other than cancer. Using biomarkers to classify patients by


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disease type or response probability can improve drug development by reducing variability and increasing the size of the treatment effect. If the biomarkers are then incorporated into clinical practice, clinical variability can also be reduced. Decreasing interindividual differences in drug exposure is another strategy to reduce response variability. Recently, FDA has approved a number of assays for genetic polymorphisms in drug-metabolizing enzymes. Many marketed drugs are subject to polymorphic metabolism, leading to a wide range of exposures in the treated population (13). The safety and effectiveness of these drugs, as well as investigational drugs with variable metabolism, could be improved by using dose adjustments directed by genetic tests. The absence of practical processes to establish the clinical significance of a given biomarker has severely limited the use of existing biomarkers in drug development and the clinic. The return on investment for diagnostic test manufacturers is seldom sufficient to enable extensive clinical trials, and investigational drugs are rarely developed in concert with new diagnostic tests. To address these issues, FDA and other stakeholders have established the concept of biomarker qualification, which means determining the clinical significance of the biomarker in a specific context (14). For example, a genetic test might be qualified to identify a subset of disease for the purpose of trial enrollment. The quantity of data needed for qualification depends on the intended use, and most uses require far less data than would be required to establish a surrogate endpoint for efficacy. Because the development and qualification of new biomarkers will benefit many parties, consortia have been formed for this purpose. “The Biomarker Consortium” (http:// www.biomarkersconsortium.org) at the Foundation for NIH (FNIH) is a leading example. Initiated by federal partners NIH, FDA, and Center for Medicare and Medicaid Services (CMS), along with private sector organizations PhRMA (the pharmaceutical

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manufacturers’ trade organization) and BIO (the Biotechnology Industry Organization), the consortium now has multiple industrial, academic, and patient group members. It is funding biomarker qualification trials for fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning in non-Hodgkin’s lymphoma and lung cancer and is evaluating a number of additional proposals.

CLINICAL TRIAL MODERNIZATION Other areas in urgent need of improvement are the design, conduct, and analysis of clinical trials during drug development. This part of the Critical Path Initiative includes establishing standards for clinical trial data and its management; fully automating trial process and data management; improving the clinical trial quality management system; and modernizing FDA oversight of the clinical trial process. Significant progress in data standardization has been achieved by the clinical trial standards organization, the Clinical Data Interchange Standards Consortium (CDISC) (http://www.cdisc.org). Working with the National Cancer Institute (NCI), FDA has adopted a number of CDISC standards for regulatory submissions. Currently, a CDISC initiative called Clinical Data Acquisitions Standards Harmonization (CDASH), organized to develop standards for case report forms, is ongoing (15). Additionally, FDA is working with the NIH to harmonize and simplify various investigator reporting requirements. Over the past several years, FDA has been modernizing its oversight of clinical trials, has held several public meetings, and has issued guidance and draft regulations. Many parties are interested in improving the consistency, quality, and reliability of clinical trials while reducing the paperwork burdens (16). Discussions about forming a public-private partnership to accomplish these objectives are also ongoing.

BIOINFORMATICS One of the greatest scientific flaws in the current process of medical product development is its failure to produce generalized knowledge despite a huge investment in data generation. For example, FDA holds the world’s largest collection of animal test data and correlated human trial data, but most of this information is unusable in its current form, except to document a specific development program. As a result, opportunities for major improvement are missed. Under the Critical Path Initiative, stakeholders are beginning to take advantage of these opportunities. For example, FDA and various partners have created a standard for a digital electrocardiogram (ECG) recording, and FDA requested that ECG data submitted to it be in this format. At the same time, a data warehouse to hold the ECG data was established. Since that time, >500,000 digital ECGs have been added to the warehouse, and a collaboration with Duke University has been established for overall data analysis (17). This resource may help scientists efficiently evaluate candidate drugs for adverse cardiac repolarization effects, a concern that is currently addressed (somewhat less than satisfactorily) by extensive clinical testing. As data standards for regulatory submissions are implemented, processes and protocols to utilize the data for research purposes without compromising proprietary interests need to be developed. One important use of such data will be to construct quantitative models of disease processes, incorporating what is known about biomarkers, clinical outcomes, and the effects of various interventions. These models can then be used for trial simulations, to better design appropriate trials and clinical outcome measures (18). Although the FDA has constructed several disease models, this work is in its early stages and will require extensive partnerships. However, there is little doubt that such quantitative approaches constitute the future of product development and assessment.

www.annualreviews.org • The FDA Critical Path Initiative

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DRUG MANUFACTURING


Perhaps surprisingly, the manufacturing of pharmaceuticals suffers from the problems of drug development in general. Many drug manufacturing processes are characterized by inefficiency, waste, and neglect of modern process control technologies. Thus, the pharmaceutical manufacturing sector would also benefit from incorporation of new science and technology. FDA is spearheading these changes through its Pharmaceutical Quality for the 21st Century Initiative (19).

CONSORTIA INVOLVED IN CRITICAL PATH ACTIVITIES After FDA’s 2004 call for public-private collaborations, scientists at several universities created programs to work with FDA to conduct the needed research. Despite limited funding, these programs have been able to make significant progress addressing projects called for in the 2006 Critical Path Opportunity List. Investments in programs created by the University of Arizona, Duke University, Massachusetts Institute of Technology (MIT), and the University of California at San Francisco are beginning to produce results (see Sidebar). The first to respond, the University of Arizona, offered to create a nonprofit research and education institute dedicated solely to work with FDA on the Critical Path

ACADEMIC CONTRIBUTIONS TO DRUG DEVELOPMENT SCIENCE The Center for Biomedical Innovation at MIT (CBI), the Center for Drug Development Sciences (CDDS) at the University of California, San Francisco, and the Duke Clinical Research Institute (DCRI) are examples of university-based centers that are making major contributions to the regulatory sciences. Because of their broad access to outstanding scientists in the academic community, they are important resources for companies that are developing medical products, and they train the innovative leaders.

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Initiative. The Arizona community (state and local governments, business, and philanthropic groups) saw this opportunity to partner with FDA as a way to leverage the state’s $2 billion investment in biotechnology. In early 2004, with a planning grant from the state, the FDA, the University of Arizona, and SRI International (a nonprofit corporation, formerly Stanford Research Institute) agreed to create the Critical Path Institute (C-Path). C-Path is envisioned as a neutral third party, without financial support from the regulated industry. Because of C-Path’s neutral funding and its mission to focus on process, not products, FDA can actively participate in the work without concerns about conflicts of interest. C-Path’s strategy is to invite stakeholders to join consortia in which they can work with the FDA to improve the process of medical product development. The University of Arizona and SRI committed “in kind” support, predominantly the time and effort of their scientists. The FDA agreed to participate under a Memorandum of Understanding. C-Path was incorporated in January 2005 and began initial operations in July 2005 with a $10 million, five-year commitment from the City of Tucson, Pima County, regional municipalities, and private foundations in Arizona (http://www.C-Path.org). C-Path has approximately 20 employees working with the FDA and industry scientists on the projects listed in Table 1. These projects were selected using three specific criteria. The first and essential requirement is that there be champions for the project within the FDA. Also, there must be two or more companies willing to work together on the project, and there must be a source of external funding that is independent of commercial interests. The projects focus on precompetitive aspects of drug development, e.g., preclinical toxicology. The first consortium formed by C-Path, the Predictive Safety Testing Consortium (PSTC), was announced in March 2006 by Secretary of Health and Human Services Michael Leavitt. Since then, the PSTC has

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C-Path Institute projects (http://www.C-Path.org)

Development gap


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C-Path process

C-Path project

Deliverables

Inconsistent technical methods employed across the industry

Create consortium and process for sharing and validation of methods

Predictive Safety Testing Consortium (PSTC)

New FDA guidances to improve and accelerate preclinical safety testing Increased safety of new drugs

Drugs, devices, and diagnostics developed separately. New cancer drugs only 10%–20% effective

Create cross-industry and cross-agency (FDA/NIH/CMS) collaborations to evaluate multiple technologies

Lung cancer diagnostics validation clinical trial with NCI, FDA, and industry

Test to predict lung cancer response Change drug label Model for future drug/diagnostic products

Drugs and diagnostics developed separately. Warfarin side effects cost ∼$1 billion/year and only half (2 million) of patients who need warfarin get treatment

Create cross-industry and cross-agency (FDA/NIH/CMS) collaborations to evaluate multiple technologies

Genomic-based dosing for warfarin, clinical trial with NHLBI, FDA, and industry

Reduce adverse events Increase indicated warfarin treatment Change warfarin label: recommend genetic test Model for future pharmacogenetic clinical trials

High failure rate of clinical trials

Create consortium of orphan disease foundations

Create disease model registries (Nieman-Pick C, valley fever, adrenal cancer)

Template for disease model-based clinical trial design and fewer failed drug development programs

grown from an initial eight to 15 global pharmaceutical companies that are sharing their preclinical methods and data for tests of nephrotoxicity, hepatotoxicity, vascular injury, and carcinogenicity. In this consortium, methods developed by one company that appear to best predict drug toxicity are verified by experiments performed by a second company. Over 160 scientists are participating, including 25 scientists from the FDA and its European counterpart, the EMEA, who participate in the meetings and discussions as advisors. The methods that are cross-validated by the companies are expected to eventually provide the scientific basis for regulatory guidance to be issued by the FDA and the EMEA. A goal of C-Path projects is to integrate new and advanced technologies into medical product development, especially those that accelerate pathways for innovative diagnostic tests and therapies. For example, C-Path’s project with the FDA and the University of Utah examines genetic tests for improved war-

farin dosage selection. The goal is to provide the scientifically based pathway for simultaneous development of drugs and genetic tests to improve a drug’s safety or effectiveness. Another of C-Path’s projects, the Molecular Assays and Targeted Therapeutics (MATT) project, is being conducted by a collaboration among the FDA, the NCI, and the CMS. MATT’s goal is to define a more rapid and efficient process for integrated development of drugs, diagnostics, imaging, and other technologies that work together to help patients with cancer. The project is exploring a regulatory path by examining the utility of diagnostics and drugs that could enable targeted therapy of non-small-cell lung cancers that overexpress the epidermal growth factor receptor. C-Path’s Disease Model Registry (DMR) for orphan drugs (i.e., drugs intended for diseases affecting 50% for hemostasis. The use of rFVIIa for treatment of bleeding in hemophilia is a new concept—a pharmacological instead of a substitution therapy. By increasing the physiological level of FVIIa, the nonspecific binding of rFVIIa to activated platelets is exploited. However, the exact relationship between the plasma concentration of FVII:C and the thrombin generation at the site of injury is not known. Furthermore, a perfect method for determining this localized effect does not exist. A number of assays for the measurement of thrombin generation have been described, but most of them measure thrombin formation in circulating blood rather than the localized thrombin. The recommended dose (90–120 μg/kg bolus i.v.) was based on test tube assays and dog experiments (16). Following the first observation that rFVIIa normalized the activated partial thromboplastin time in plasma from hemophilia patients with inhibitors if a concentration of 3.8 μg/ml was used, similar doses of human rFVIIa were found to normalize the cuticle bleeding time in dogs with hemophilia A and B (6). Taking into account a recovery (FVII:C at 10 min after injection) of 40%–50% (17; see also 14), this would approximately correspond to a concentration of 40 nM of rFVIIa in plasma. The concentration of rFVIIa required to start thrombin generation on preactivated platelets in the cellbased in vitro hemostasis model was 50 nM (6). Despite these results, the doses initially used in hemophilia patients were lower. Clearance rate, recovery at 10 min after injection, and the capacity to generate thrombin on the platelet surface vary widely among individuals (14), so the optimal dose might show great variation in a wider population. The clearance rate in children below 15 years of age may be as much as three times the normal rate for adults, which suggests that they may require higher doses of rFVIIa in order to ensure formation of the firm, tight initial hemostatic plug that is necessary for maintaining hemostasis (14). Recently, a dose of 270 μg/kg was approved in Europe on the basis of a study comparing


FVII:C: FVII concentration in plasma

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90 μg/kg three times per bleed with one single bolus of 270 μg/kg (11).

Effect of rFVIIa as Prophylaxis Several patients with severe hemophilia complicated by inhibitors against FVIII or FIX have been successfully treated with repeated daily doses of rFVIIa (18). These patients had all developed “target joints,” i.e., joints in which frequent bleeds had resulted in chronic swelling, inflammatory synovitis, and a tendency toward further bleeding. Bleedings in such a joint require a stable hemostatic plug for full hemostasis. Results in these patients supported the idea that rFVIIa could be used for prevention of chronic hemophilic arthropathy in hemophilia patients with inhibitors. In a recently published randomized prospective clinical trial (18a), rFVIIa was administered once daily in doses of 90 μg/kg or 270 μg/kg for three months. With oncedaily dosing of rFVIIa, the number of bleeds decreased, not only during the three-month treatment period but also during the observation period that followed (three months of no regular treatment). This outcome may mark another step toward the goal of making the treatment of hemophilia patients with inhibitors similar to that of noninhibitor patients. The decrease in bleeding during the treatment period was probably due to prevention of the repeated bleedings in target joints, resulting in amelioration of the inflammatory synovitis. However, it is not clear how this effect was achieved by once-daily administration of an agent with a plasma T/2 of 2–3 h. Another question related to this short halflife is why rFVIIa prophylaxis reduces the number of hemorrhagic events in the posttreatment period. Although this phenomenon may be due simply to a decrease in the inflammatory response, evidence related to the extravascular distribution of FVIIa suggests that extravascular coagulation may also play an important role in the prolonged reduction of bleeding episodes in hemophilia patients with


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inhibitors treated repeatedly on a long-term basis with rFVIIa. Already in 1974 it was shown that fibrinopeptides are continuously cleaved from fibrinogen at low levels in normal individuals (3). Furthermore, activation peptides from FIX, FX, and prothrombin have been identified in the blood of normal individuals. There is also abundant evidence for the presence of many coagulation proteins in the extravascular space (18). Functional FVIIaTF complexes were also demonstrated in an umbilical vein model system (18) as well as around dermal vessels in mice (5). A hypothesis to account for a prophylactic effect of rFVIIa would be that some of the injected rFVIIa reaches the extravascular space and increases the local concentration in this compartment, which may then facilitate the formation of rFVIIa-TF complexes. In vitro studies have shown that FVIIa-TF complexes form on cell surfaces and that the bound FVIIa is internalized and partially degraded in the cell. However, some of it will reappear on the cell surface and bind to TF recruited from the Golgi to the cell surface. The amount of FVIIa internalized is directly proportional to the amount of FVIIa bound to cell surface TF, and the process may continue for a long time if there is plenty of FVIIa present in the extravascular compartment (18). Assuming that a similar process occurs in vivo, continuous formation of rFVIIa-TF complexes on extravascular cell surfaces may facilitate thrombin generation on platelets that plug the leak in small blood vessels. Another possibility is that rFVIIa administered in pharmacological doses may bind to some other protein or compound on the vessel walls and serve as a reservoir for complex formation at any exposure of TF, thereby facilitating the formation of a hemostatic plug by increasing thrombin generation on activated platelets.

Clinical Experience with rFVIIa Other Than in Hemophilia Patients The ability of rFVIIa to enhance thrombin generation on the surface of activated platelets

makes it a potential hemostatic agent in any situation that requires the formation of a tight hemostatic plug. In the cell-based model, rFVIIa was shown to cause a dose-dependent shortening of the lag phase of platelet activation in the presence of platelet counts down to at least 10,000 μl−1 . Also a tighter fibrin structure was observed in the presence of rFVIIa and low platelet counts. Furthermore, the addition of rFVIIa to whole blood made thrombocytopenic (150 similar cases, recognizing Mendelian inheritance with cosegregation of dolichostenomelia, ectopia lentis, and mitral valve disease (2). The cardiac manifestations were described by Victor A. McKusick in 1955, who reported dilatation and dissection of the aorta and aortic valve regurgitation in MFS, which he classified among the heritable disorders of connective tissue (3). Despite these reports, the diagnosis of MFS was somewhat variable until the mid1980s. At the 1986 International Congress of Human Genetics in Berlin, consensus opinions were compiled regarding the clinical diagnosis (4). This conference led to a series of diagnostic criteria that attempted to draw distinctions within a broad spectrum of connective tissue disorders that showed overlap with the phenotypes seen in MFS. Accurate phenotypic assignment was important in subsequent linkage analyses and the eventual recognition that MFS is caused by mutations Judge

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in FBN1, the gene encoding the extracellular matrix protein fibrillin-1 (5, 6). However, the Berlin Nosology for the diagnosis of MFS was later recognized to be inappropriately inclusive of individuals with mild features within families segregating MFS (7). In 1996, revised diagnostic criteria for MFS were proposed, with continued reliance on a series of major and minor clinical manifestations in different organ systems (8). These criteria were more stringent (Table 1); they required at least four of eight skeletal features for assignment of the skeletal system as a major criterion, potentially included molecular testing, and increased requirements for family members of an unequivocally affected individual. Although it is currently estimated that >90% of people with classic MFS will have a definable FBN1 mutation, the large size of this gene and the extreme allelic heterogeneity characteristic of MFS have frustrated efficient molecular diagnosis for this disorder (9). More importantly, many other conditions, such as mitral valve prolapse syndrome, MASS phenotype, familial ectopia lentis, Weill-Marchesani syndrome, and Shprintzen-Goldberg syndrome, have also been associated with mutations in FBN1 (10–14). It is often difficult or impossible to predict the phenotype from the character or location of a mutation. Mutation analysis is best used to determine if a presymptomatic individual has inherited the predisposition for a defined phenotype seen in the extended family. Although mutation testing can serve as an adjunct, diagnosis of MFS in a proband is currently made on clinical grounds. An important consideration in the differential diagnosis of MFS is a recently described condition known as Loeys-Dietz syndrome (LDS) (15). LDS is caused by heterozygous mutations in the genes encoding the transforming growth factor (TGFβ) receptors 1 and 2 (TGFBR1 or TGFBR2) (15). These mutations result in increased TGFβ signaling in both cells and involved tissues from affected patients (15). This disorder shares

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Table 1

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Diagnostic criteria for Marfan syndrome

Index case: • If the family/genetic history is not contributory, major criteria in ≥2 different organ systems and involvement of a third organ system. • If a mutation known to cause Marfan syndrome in others is detected, 1 major criterion in an organ system and involvement of a second organ system. Relative of an index case: • Presence of a major criterion in the family history, 1 major criterion in an organ system, and involvement of a second organ system.


Organ systems: Skeletal: Major criteria: The presence of at least 4 of the following constitutes a major criterion in the skeletal system. • Pectus carinatum (protrusion of sternum) • Pectus excavatum (depression of sternum) requiring surgery • Reduced upper- to lower-segment ratio or arm span–to–height ratio >1.05 • Wrist and thumb signs • Scoliosis of >20◦ or spondylolisthesis (displacement of vertebra, usually in lumbar spine) • Reduced extension at the elbows (3.0. Enrolled subjects will receive either a beta blocker (atenolol) or ARB (losartan) for a period of three years. The primary outcome will be the rate of change in normalized aortic root size. Secondary outcomes will include size and rate of change in other segments of aorta; time to aortic dissection, surgery, or death; and measures of cardiac size and aortic stiffness. Several studies have shown the ability of antibodies that antagonize TGFβ to modulate manifestations of MFS in mice, including defective pulmonary alveolar septation, myxomatous atrioventricular valves, skeletal muscle myopathy, and aortic root aneurysms (32–34, 41). A humanized anti-TGFβ1 monoclonal antibody (CAT-192) has been produced and is currently under investigation for treatment of other disorders in which this cytokine has been determined to play a pathogenetic


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role (73). Direct inhibition of TGFβ with neutralizing antibodies remains a promising strategy to ameliorate many manifestations of MFS. Insights derived from the study of MFS may prove relevant to other conditions. The finding that other inherited arteriopathies (LDS, arterial tortuosity syndrome, and autosomal recessive cutis laxa) also relate to excessive TGFβ signaling (15, 74, 75) suggests that this may be a common final pathway for aneurysm formation, and that ARBs may prove effective regardless of the underlying reason for aneurysm. There is already evidence derived from a mouse model of Duchenne muscular dystrophy that losartanmediated restoration of muscle regeneration, architecture, and function (as initially observed in MFS) may develop into a productive treatment strategy (41).

CONCLUSIONS Successful treatment of MFS relies on several important steps: first, recognition of the disorder with anticipation of potential complications; second, early intervention with activity restrictions and pharmacologic therapies; and third, surgical intervention when appropriate. Investigation of the pathophysiologic basis for many aspects of MFS in murine models has led to remarkable insights. We anticipate that translation of these research discoveries to clinical trials will demonstrate effectiveness of a pharmacologic approach in which target selection is based on our improved understanding of the molecular basis for pathologic features of this condition.

SUMMARY POINTS 1. The diagnosis of Marfan syndrome is made through clinical criteria (Table 1). It is important to exclude the diagnosis of Loeys-Dietz syndrome (Table 2). 2. Many manifestations of Marfan syndrome, including aortic aneurysm, are caused by increased activation of and signaling by transforming growth factor beta (TGFβ).

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3. For individuals with Marfan syndrome, we advise moderation in aerobic activity and avoidance of isometric exercise. 4. Beta-adrenergic receptor blockers appear to slow pathologic aortic root growth, but the data supporting their use is limited.


5. Elective repair of aortic root aneurysm is recommended with aortic root diameter of 5 cm or greater in adults with Marfan syndrome. Guidelines for surgery in children are less precise and require a more individualized approach. 6. Because of high lifetime risk of infective endocarditis, as well as high risk for adverse outcomes in the setting of endocarditis, we continue to advise patients with Marfan syndrome and other connective tissue disorders who have myxomatous valves or valvesparing aortic root surgery to use antibiotic prophylaxis for dental, gastrointestinal, and genitourinary procedures. 7. Angiotensin II type 1 (AT1) receptor blockers such as losartan prevent pathologic aortic root growth, normalize aortic wall architecture and thickness, and improve noncardiovascular manifestations such as pulmonary and skeletal muscle pathology in a murine model of Marfan syndrome. Clinical trials are under way to test the efficacy of this treatment in people with Marfan syndrome.

DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS The authors acknowledge the William S. Smilow Center for Marfan Syndrome Research, the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases, and the National Marfan Foundation.

LITERATURE CITED 1. Marfan A-B. 1896. Un cas de deformation congenitale des quarte membres plus prononcée aux extremités caracterisée par l’allongement des os avec un certain degrè d’amincissement. Bull. Mem. Soc. Med. Hop. Paris 13:220–26 2. Marfan A-B. 1938. La dolichosténomélie [dolichomélie arachnodactylie]. Ann. Med. 44:5– 29 3. McKusick VA. 1955. The cardiovascular aspects of Marfan’s syndrome. Circulation 11:321 4. Beighton P, de Paepe A, Danks D, et al. 1988. International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am. J. Med. Genet. 29:581–94 5. Dietz HC, Pyeritz RE, Hall BD, et al. 1991. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15–q21.3. Genomics 9:355–61 6. Dietz HC, Cutting GR, Pyeritz RE, et al. 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–39 www.annualreviews.org • Therapy of Marfan Syndrome

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7. Pereira L, Levran O, Ramirez F, et al. 1994. A molecular approach to the stratification of cardiovascular risk in families with Marfan’s syndrome. N. Engl. J. Med. 331:148–53 8. De Paepe A, Devereux RB, Dietz HC, et al. 1996. Revised diagnostic criteria for the Marfan syndrome. Am. J. Med. Genet. 62:417–26 9. Loeys B, De Backer J, Van Acker P, et al. 2004. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum. Mutat. 24:140–46 10. Glesby MJ, Pyeritz RE. 1989. Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA 262:523–28 11. Montgomery RA, Geraghty MT, Bull E, et al. 1998. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am. J. Hum. Genet. 63:1703–11 12. Kainulainen K, Karttunen L, Puhakka L, et al. 1994. Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome. Nat. Genet. 6:64–69 13. Faivre L, Gorlin RJ, Wirtz MK, et al. 2003. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J. Med. Genet. 40:34–36 14. Sood S, Eldadah ZA, Krause WL, et al. 1996. Mutation in fibrillin-1 and the Marfanoidcraniosynostosis (Shprintzen-Goldberg) syndrome. Nat. Genet. 12:209–11 15. Loeys BL, Chen J, Neptune ER, et al. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37:275–81 16. Loeys BL, Schwarze U, Holm T, et al. 2006. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355:788–98 17. Halme T, Savunen T, Aho H, et al. 1985. Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia. Exp. Mol. Pathol. 43:1–12 18. Tsuji T. 1986. Marfan syndrome: demonstration of abnormal elastic fibers in skin. J. Cutan. Pathol. 13:144–53 19. Kainulainen K, Pulkkinen L, Savolainen A, et al. 1990. Location on chromosome 15 of the gene defect causing Marfan syndrome. N. Engl. J. Med. 323:935–39 20. Sakai LY, Keene DR, Engvall E. 1986. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell. Biol. 103:2499–509 21. Hollister DW, Godfrey M, Sakai LY, et al. 1990. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N. Engl. J. Med. 323:152–59 22. Kielty CM, Shuttleworth CA. 1995. Fibrillin-containing microfibrils: structure and function in health and disease. Int. J. Biochem. Cell Biol. 27:747–60 23. Dietz HC, McIntosh I, Sakai LY, et al. 1993. Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics 17:468–75 24. Schrijver I, Liu W, Odom R, et al. 2002. Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. Am. J. Hum. Genet. 71:223–37 25. Frischmeyer PA, Dietz HC. 1999. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8:1893–900 26. Montgomery RA, Dietz HC. 1997. Inhibition of fibrillin 1 expression using U1 snRNA as a vehicle for the presentation of antisense targeting sequence. Hum. Mol. Genet. 6:519–25 27. Judge DP, Biery NJ, Keene DR, et al. 2004. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114:172–81 28. Pereira L, Andrikopoulos K, Tian J, et al. 1997. Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat. Genet. 17:218–22


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29. Hutchinson S, Furger A, Halliday D, et al. 2003. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum. Mol. Genet. 12:2269–76 30. Sinha S, Nevett C, Shuttleworth CA, et al. 1998. Cellular and extracellular biology of the latent transforming growth factor-beta binding proteins. Matrix Biol. 17:529–45 31. Isogai Z, Ono RN, Ushiro S, et al. 2003. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278:2750–57 32. Neptune ER, Frischmeyer PA, Arking DE, et al. 2003. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33:407–11 33. Ng CM, Cheng A, Myers LA, et al. 2004. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J. Clin. Invest. 114:1586–92 34. Habashi JP, Judge DP, Holm TM, et al. 2006. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117–21 35. Massague J, Seoane J, Wotton D. 2005. Smad transcription factors. Genes. Dev. 19:2783– 810 36. Rodriguez-Vita J, Sanchez-Lopez E, Esteban V, et al. 2005. Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-betaindependent mechanism. Circulation 111:2509–17 37. Lavoie P, Robitaille G, Agharazii M, et al. 2005. Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J. Hypertens. 23:1895–903 38. Houlihan CA, Akdeniz A, Tsalamandris C, et al. 2002. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction. Diab. Care 25:1072–77 39. Daugherty A, Manning MW, Cassis LA. 2000. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J. Clin. Invest. 105:1605–12 40. Daugherty A, Manning MW, Cassis LA. 2001. Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br. J. Pharmacol. 134:865–70 41. Cohn RD, van Erp C, Habashi JP, et al. 2007. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13:204–10 42. Maron BJ, Chaitman BR, Ackerman MJ, et al. 2004. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 109:2807–16 43. Braverman AC. 1998. Exercise and the Marfan syndrome. Med. Sci. Sports Exerc. 30:S387– 95 44. Halpern BL, Char F, Murdoch JL, et al. 1971. A prospectus on the prevention of aortic rupture in the Marfan syndrome with data on survivorship without treatment. Johns Hopkins Med. J. 129:123–29 45. Salim MA, Alpert BS, Ward JC, et al. 1994. Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am. J. Cardiol. 74:629–33 46. Rossi-Foulkes R, Roman MJ, Rosen SE, et al. 1999. Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am. J. Cardiol. 83:1364–68 www.annualreviews.org • Therapy of Marfan Syndrome

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47. Shores J, Berger KR, Murphy EA, et al. 1994. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N. Engl. J. Med. 330:1335–41 48. Ladouceur M, Fermanian C, Lupoglazoff J-M, et al. 2007. Effect of beta-blockade on ascending aortic dilatation in children with the Marfan syndrome. Am. J. Cardiol. 99:406– 9 49. Gersony DR, McClaughlin MA, Jin Z, et al. 2007. The effect of beta-blocker therapy on clinical outcome in patients with Marfan’s syndrome: a meta-analysis. Int. J. Cardiol. 114:303–8 50. Dahlof C, Dimenas E, Kendall M, et al. 1991. Quality of life in cardiovascular diseases. Emphasis on beta-blocker treatment. Circulation 84:VI108–18 51. Gleiter CH, Deckert J. 1996. Adverse CNS-effects of beta-adrenoceptor blockers. Pharmacopsychiatry 29:201–11 52. Yetman AT, Bornemeier RA, McCrindle BW. 2005. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am. J. Cardiol. 95:1125–27 53. Takai S, Jin D, Sakaguchi M, et al. 1999. Chymase-dependent angiotensin II formation in human vascular tissue. Circulation 100:654–58 54. Murdoch JL, Walker BA, Halpern BL, et al. 1972. Life expectancy and causes of death in the Marfan syndrome. N. Engl. J. Med. 286:804–8 55. Silverman DI, Burton KJ, Gray J, et al. 1995. Life expectancy in the Marfan syndrome. Am. J. Cardiol. 75:157–60 56. Bentall H, De Bono A. 1968. A technique for complete replacement of the ascending aorta. Thorax 23:338–39 57. Cabrol C, Pavie A, Gandjbakhch I, et al. 1981. Complete replacement of the ascending aorta with reimplantation of the coronary arteries: new surgical approach. J. Thorac. Cardiovasc. Surg. 81:309–15 58. Svensson LG, Crawford ES, Hess KR, et al. 1992. Composite valve graft replacement of the proximal aorta: comparison of techniques in 348 patients. Ann. Thorac. Surg. 54:427–37; discussion 438–39 59. Ross DN. 1967. Replacement of aortic and mitral valves with a pulmonary autograft. Lancet 290:956–58 60. Luciani GB, Casali G, Favaro A, et al. 2003. Fate of the aortic root late after Ross operation. Circulation 108:II-61–67 61. Gott VL, Greene PS, Alejo DE, et al. 1999. Replacement of the aortic root in patients with Marfan’s syndrome. N. Engl. J. Med. 340:1307–13 62. Sarsam MA, Yacoub M. 1993. Remodeling of the aortic valve anulus. J. Thorac. Cardiovasc. Surg. 105:435–38 63. David TE, Feindel CM. 1992. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta. J. Thorac. Cardiovasc. Surg. 103:617– 21; discussion 22 64. Miller DC. 2007. Valve-sparing aortic root replacement: current state of the art and where are we headed? Ann. Thorac. Surg. 83:S736–39; discussion S85–90 65. Patel ND, Williams JA, Barreiro CJ, et al. 2006. Valve-sparing aortic root replacement: early experience with the De Paulis Valsalva graft in 51 patients. Ann. Thorac. Surg. 82:548– 53 66. David TE, Feindel CM, Webb GD, et al. 2006. Long-term results of aortic valve-sparing operations for aortic root aneurysm. J. Thorac. Cardiovasc. Surg. 132:347–54


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67. Bethea BT, Fitton TP, Alejo DE, et al. 2004. Results of aortic valve-sparing operations: experience with remodeling and reimplantation procedures in 65 patients. Ann. Thorac. Surg. 78:767–72 68. Dajani AS, Taubert KA, Wilson W, et al. 1997. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 277:1794–801 69. Wilson W, Taubert KA, Gewitz M, et al. 2007. Prevention of infective endocarditis. Guidelines from the American Heart Association. Circulation. Epub ahead of print 70. Thiene G, Basso C. 2006. Pathology and pathogenesis of infective endocarditis in native heart valves. Cardiovasc. Pathol. 15:256–63 71. Naito T, Masaki T, Nikolic-Paterson DJ, et al. 2004. Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK: a mechanism for activation of latent TGF-beta1. Am. J. Physiol. Renal Physiol. 286:F278–87 72. Lawler J, Sunday M, Thibert V, et al. 1998. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J. Clin. Invest. 101:982– 92 73. Denton CP, Merkel PA, Furst DE, et al. 2007. Recombinant human antitransforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56:323–33 74. Coucke PJ, Willaert A, Wessels MW, et al. 2006. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat. Genet. 38:452–57 75. Hanada K, Vermeij M, Garinis GA, et al. 2007. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ. Res. 100:738–46

RELATED RESOURCES National Marfan Foundation, http://www.marfan.org, 22 Manhasset Avenue, Port Washington, NY 11050; 1-800-862-7326

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Annual Review of Medicine


Contents

Volume 59, 2008

The FDA Critical Path Initiative and Its Influence on New Drug Development Janet Woodcock and Raymond Woosley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Reversing Advanced Heart Failure by Targeting Ca2+ Cycling David M. Kaye, Masahiko Hoshijima, and Kenneth R. Chien p p p p p p p p p p p p p p p p p p p p p p p p 13 Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis Ulla Hedner and Mirella Ezban p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Therapy of Marfan Syndrome Daniel P. Judge and Harry C. Dietz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 43 Preeclampsia and Angiogenic Imbalance Sharon Maynard, Franklin H. Epstein, and S. Ananth Karumanchi p p p p p p p p p p p p p p p p p 61 Management of Lipids in the Prevention of Cardiovascular Events Helene Glassberg and Daniel J. Rader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 79 Genetic Susceptibility to Type 2 Diabetes and Implications for Antidiabetic Therapy Allan F. Moore and Jose C. Florez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 95 Array-Based DNA Diagnostics: Let the Revolution Begin Arthur L. Beaudet and John W. Belmont p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p113 Inherited Mitochondrial Diseases of DNA Replication William C. Copeland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p131 Childhood Obesity: Adrift in the “Limbic Triangle” Michele L. Mietus-Snyder and Robert H. Lustig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147 Expanded Newborn Screening: Implications for Genomic Medicine Linda L. McCabe and Edward R.B. McCabe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p163 Is Human Hibernation Possible? Cheng Chi Lee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p177 Advance Directives Linda L. Emanuel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p187 v

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Genetic Determinants of Aggressive Breast Cancer Alejandra C. Ventura and Sofia D. Merajver p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199 A Role for JAK2 Mutations in Myeloproliferative Diseases Kelly J. Morgan and D. Gary Gilliland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p213 Appropriate Use of Cervical Cancer Vaccine Gregory D. Zimet, Marcia L. Shew, and Jessica A. Kahn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p223 A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkin’s Lymphoma Arturo Molina p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p237


Nanotechnology and Cancer James R. Heath and Mark E. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p251 Cancer Epigenetics: Modifications, Screening, and Therapy Einav Nili Gal-Yam, Yoshimasa Saito, Gerda Egger, and Peter A. Jones p p p p p p p p p p p p267 T Cells and NKT Cells in the Pathogenesis of Asthma Everett H. Meyer, Rosemarie H. DeKruyff, and Dale T. Umetsu p p p p p p p p p p p p p p p p p p p p281 Complement Regulatory Genes and Hemolytic Uremic Syndromes David Kavanagh, Anna Richards, and John Atkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p293 Mesenchymal Stem Cells in Acute Kidney Injury Benjamin D. Humphreys and Joseph V. Bonventre p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p311 Asthma Genetics: From Linear to Multifactorial Approaches Stefano Guerra and Fernando D. Martinez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p327 The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in Human Disease Stavros Garantziotis, John W. Hollingsworth, Aimee K. Zaas, and David A. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p343 Advances in Antifungal Therapy Carole A. Sable, Kim M. Strohmaier, and Jeffrey A. Chodakewitz p p p p p p p p p p p p p p p p p p361 Herpes Simplex: Insights on Pathogenesis and Possible Vaccines David M. Koelle and Lawrence Corey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381 Medical Management of Influenza Infection Anne Moscona p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p397 Bacterial and Fungal Biofilm Infections A. Simon Lynch and Gregory T. Robertson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p415 EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story Lecia V. Sequist and Thomas J. Lynch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p429 Adaptive Treatment Strategies in Chronic Disease Philip W. Lavori and Ree Dawson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443 vi

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Antiretroviral Drug–Based Microbicides to Prevent HIV-1 Sexual Transmission Per Johan Klasse, Robin Shattock, and John P. Moore p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p455 The Challenge of Hepatitis C in the HIV-Infected Person David L. Thomas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p473 Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection Luc Geeraert, Günter Kraus, and Roger J. Pomerantz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p487


Advancements in the Treatment of Epilepsy B.A. Leeman and A.J. Cole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p503 Indexes Cumulative Index of Contributing Authors, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p525 Cumulative Index of Chapter Titles, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p529 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://med.annualreviews.org/errata.shtml

Contents

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Preeclampsia and Angiogenic Imbalance Sharon Maynard,1 Franklin H. Epstein,2 and S. Ananth Karumanchi2 1

Renal Division, Department of Medicine, George Washington University School of Medicine; 2 Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; email: [email protected]

Annu. Rev. Med. 2008. 59:61–78

Key Words

First published online as a Review in Advance on October 15, 2007

hypertension in pregnancy, VEGF, sFlt1, endothelial dysfunction

The Annual Review of Medicine is online at http://med.annualreviews.org This article’s doi: 10.1146/annurev.med.59.110106.214058 c 2008 by Annual Reviews. Copyright All rights reserved 0066-4219/08/0218-0061$20.00

Abstract Preeclampsia is a systemic syndrome of pregnancy that originates in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of preeclampsia was largely unknown, but recent work suggests a key role for altered expression of placental antiangiogenic factors. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These antiangiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and the role of angiogenic proteins in early placental vascular development is just beginning to be explored. These discoveries have exciting clinical implications and are likely to transform the detection and treatment of preeclampsia in the future.

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INTRODUCTION


Preeclampsia is a systemic syndrome that occurs in pregnant women. It is characterized by the new onset of hypertension and proteinuria usually after 20 weeks gestation. Preeclampsia affects ∼3%–5% of pregnancies worldwide (1). Despite many advances in our understanding of the pathophysiology of preeclampsia, delivery of the placenta remains the only definitive treatment. Preeclampsia is a leading cause of preterm birth and consequent neonatal morbidity and mortality in the developed world. In developing countries, where access to safe, emergent delivery is less readily available, preeclampsia claims the lives of >60,000 mothers every year (1). This article describes recent discoveries concerning the pathogenesis of preeclampsia, with emphasis on the emerging role of angiogenic factors as potential mediators of the clinical signs and symptoms of preeclampsia. This work clarifies the pathogenesis of this enigmatic disease and holds promise for the prediction, prevention, and treatment of preeclampsia.

centa is a product of both mother and father (5). Several large genome-wide scans seeking a specific linkage to preeclampsia have been fairly discordant and disappointing, with significant LOD scores in isolated Finnish (2p25, 9p13) (6) and Icelandic (2p12) (7) populations. Specific genetic mutations consistent with these loci have not been identified. Several medical conditions are associated with increased preeclampsia risk, including chronic hypertension, diabetes mellitus, renal disease, obesity, and hypercoagulable states. Women with preeclampsia in a prior pregnancy have a high risk of preeclampsia in subsequent pregnancies. Conditions associated with increased placental mass, such as multifetal gestations and hyatidiform mole, also are associated with increased preeclampsia risk. Interestingly, smoking during pregnancy is thought to reduce the risk of preeclampsia (8). Although none of these risk factors is fully understood, they have provided insights into pathogenesis.

CLINICAL FEATURES EPIDEMIOLOGY AND RISK FACTORS Most cases of preeclampsia occur in healthy, nulliparous women, in whom the incidence of preeclampsia may be as high as 7.5%. Although it is classically a disorder of first pregnancies, multiparous women who are pregnant with a new partner are said to have an elevated preeclampsia risk similar to that of nulliparous women (2). This effect may be due to increased interpregnancy interval rather than the change in paternity per se (3). Although most cases of preeclampsia occur in the absence of a family history, the presence of preeclampsia in a first-degree relative increases a woman’s risk of severe preeclampsia two- to fourfold (4), suggesting a genetic contribution to the disease. A history of preeclampsia in the father’s mother also confers an increased risk, recalling that the pla62

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The new onset of hypertension and proteinuria are the cardinal features of preeclampsia. The severity of hypertension in preeclampsia can vary widely, from mild blood pressure elevations easily managed with bed rest, to severe hypertension resistant to multiple medications, often associated with headache and visual changes. The degree of proteinuria in preeclampsia also varies, from minimal to nephrotic range. Occasionally, gestational hypertension without proteinuria is associated with features of severe preeclampsia, such as alterations in liver function, hemolysis, or seizures (9). Although edema was historically part of the diagnostic triad for preeclampsia, it is also a common feature of normal pregnancy, diminishing its usefulness as a specific pathological sign. Still, the sudden onset of severe edema–especially edema of the hands and face–can be an important symptom in this


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otherwise insidious disease and is often the only change detectable by the patient. Serum uric acid is elevated in preeclampsia primarily as a result of enhanced tubular urate reabsorption. Hyperuricemia may contribute to the pathogenesis of preeclampsia by inducing endothelial dysfunction (10). Serum uric acid levels are correlated with the presence and severity of preeclampsia and with adverse pregnancy outcomes (11), even in gestational hypertension without proteinuria (12). Nevertheless, uric acid is of limited clinical utility in either distinguishing preeclampsia from other hypertensive disorders of pregnancy or predicting adverse outcomes (13). Uncommon but serious complications of preeclampsia include acute renal failure, seizures, pulmonary edema, acute liver injury, hemolysis, and/or thrombocytopenia. The latter three signs frequently occur together as part of the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. The HELLP syndrome is considered a severe variant of preeclampsia and is associated with a higher risk of maternal and neonatal adverse outcomes than preeclampsia alone. Seizures (eclampsia) complicate ∼2% of preeclampsia cases in the United States. Although eclampsia most often occurs in the setting of hypertension and proteinuria, it can occur without these warning signs. Up to one third of eclampsia cases occur postpartum, sometimes days to weeks after delivery (14). Complications affecting the developing fetus and the neonate include iatrogenic prematurity (and its associated sequelae), fetal growth restriction, oligohydramnios, and placental abruption. Although the exact pathogenesis of these complications is unknown, impaired uteroplacental blood flow or placental infarction are likely to contribute.

Maternal and Neonatal Mortality Approximately 500,000 women die in childbirth each year worldwide, and preeclampsia/eclampsia is estimated to account for 10%–15% of these deaths. Maternal death is

most often due to eclampsia, cerebral hemorrhage, renal failure, hepatic failure, or the HELLP syndrome. Adverse maternal outcomes can often be avoided with timely delivery; hence, in the developed world, the burden of morbidity and mortality falls on the neonate.Worldwide, preeclampsia is associated with a perinatal and neonatal mortality rate of 10% (15). Neonatal death is most commonly due to iatrogenic premature delivery undertaken to preserve the health of the mother, but it can also result from placental abruption or intrauterine fetal death.

HELLP: hemolysis, elevated liver enzymes, and low platelets

Long-Term Cardiovascular Complications Traditionally, women with preeclampsia have been reassured that the syndrome remits completely after delivery, with no long-term consequences aside from increased preeclampsia risk in future pregnancies. Epidemiologic studies have tempered this claim. Approximately 20% of women with preeclampsia develop hypertension or microalbuminuria within seven years of a pregnancy complicated by preeclampisa, compared with only 2% among women with uncomplicated pregnancies (16). The long-term risk of cardiovascular and cerebrovascular disease is doubled in women with preeclampsia and gestational hypertension compared with age-matched controls (17, 18). This increase in subsequent cardiovascular disease is observed for both preeclampsia and gestational hypertension (17), suggesting either common risk factors or a common pathophysiology in these two syndromes. Severe preeclampsia, recurrent preeclampsia, preeclampsia with preterm birth, and preeclampsia with intrauterine growth restriction (IUGR) are most strongly associated with adverse cardiovascular outcomes. Preeclampsia, especially in association with low birthweight, also carries an increased risk of later maternal kidney disease requiring a kidney biopsy (19). Preeclampsia and cardiovascular disease share many common risk factors, such as

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chronic hypertension, diabetes, obesity, renal disease, and the metabolic syndrome. Still, the increase in long-term cardiovascular mortality holds even for women who develop preeclampsia in the absence of any overt vascular risk factors. Whether the increase in long-term cardiovascular events results from vascular damage or persistent endothelial dysfunction caused by preeclampsia, or instead reflects the common risk factors shared by preeclampsia and cardiovascular disease, remains speculative.


HIF: hypoxia-inducible factor

PLACENTAL VASCULAR DEVELOPMENT The Role of the Placenta Observational evidence suggests the placenta has a central role in preeclampsia. Preeclampsia only occurs in the presence of a placenta— though not necessarily a fetus, as in the case of hyatidiform mole—and almost always remits after its delivery. In a case of preeclampsia with extrauterine pregnancy, removal of the fetus alone was not sufficient; symptoms persisted until the placenta was delivered (20). Cases of postpartum eclampsia have been associated with retained placental fragments, with rapid improvement after uterine curettage (21). Severe preeclampsia is associated with pathologic evidence of placental hypoperfusion and ischemia. Findings include acute atherosis, a lesion of diffuse vascular obstruction that includes fibrin deposition, intimal thickening, necrosis, atherosclerosis, and endothelial damage. Placental infarcts, probably due to occlusion of maternal spiral arteries, are also common. Although these findings are not universal, they appear to be correlated with severity of clinical disease (22). Abnormal uterine artery Doppler ultrasound, consistent with decreased uteroplacental perfusion, is observed before the clinical onset of preeclampsia. Unfortunately, this finding is nonspecific, so it is not diagnostically useful if used alone (23). In women residing at high altitude (24), there are alterations 64

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in placental hypoxia-inducible factor (HIF) and its targets similar to those seen in women with preeclampsia (25, 26) (see below). This observation suggests that hypoxia may be a contributing factor in preeclampsia pathogenesis. Hypertension and proteinuria can be induced by constriction of uterine blood flow in pregnant primates and other mammals (27, 28). These observations suggest that placental ischemia may be an early event in preeclampsia, at least in some patients. However, evidence that placental ischemia causes preeclampsia remains circumstantial, and several observations call the hypothesis into question. For example, the animal models based on uterine hypoperfusion fail to induce several of the multiorgan features of preeclampsia, including seizures and the HELLP syndrome. In most cases of preeclampsia, there is no evidence of growth restriction or fetal intolerance of labor, expected consequences of placental ischemia. Conversely, cases of fetal growth restriction, where placental insufficiency is the rule, often occur without preeclampsia. Hence, overt placental ischemia may be neither universal nor specific for preeclampsia but instead may be an important secondary event observed in severe cases.

Placental Vascular Remodeling Early in normal placental development, extravillous cytotrophoblasts invade the uterine spiral arteries of the decidua and myometrium. These invasive fetal cells replace the endothelial layer of the uterine vessels, transforming them from small resistance vessels to flaccid, high-caliber capacitance vessels (Figure 1). This vascular transformation allows the increase in uterine blood flow needed to sustain the fetus through the pregnancy. In preeclampsia, this transformation is incomplete. Cytotrophoblast invasion of the arteries is limited to the superficial decidua, and the myometrial segments remain narrow (29). Fisher et al. have shown that in normal placental development, invasive

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Figure 1


Placentation abnormalities in preeclampsia (from Reference 97 with permission). In normal placental development (top), invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, transforming them into high-caliber capacitance vessels capable of providing adequate placental perfusion to sustain the growing fetus. During this process, the cytotrophoblasts take on an endothelial phenotype (pseudovasculogenesis). In preeclampsia (bottom), cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the spiral arteries is shallow and they remain small-caliber resistance vessels.

cytotrophoblasts downregulate the expression of adhesion molecules characteristic of their epithelial cell origin and adopt an endothelial cell-surface adhesion phenotype, a process dubbed pseudovasculogenesis (30) or vascular mimicry. In preeclampsia, cytotrophoblasts do not undergo this switching of cell-surface integrins and adhesion molecules, and they fail to adequately invade the myometrial spiral arteries (31).

The factors that regulate this process are just beginning to be elucidated. Angiogenic factors, including Flt1 (VEGFR-1), VEGFR-2, Tie-1, and Tie-2, are essential for normal placental vascular development; mice deficient in these receptors have defective placental vasculogenesis and die in utero (32). HIF-1, which modulates expression of these angiogenic proteins, is increased in preeclampsia. Invasive cytotrophoblasts


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express several other angiogenic factors, also regulated by HIF, including vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and VEGFR-1 (Flt1); expression of these proteins by immunolocalization is altered in preeclampsia (33). Another HIF target, transforming growth factor beta3 (TGF-β3), may block cytotrophoblast invasion (34). A genetic study recently identified polymorphisms in STOX1, a paternally imprinted gene and member of the winged helix gene family, in a Dutch preeclampsia cohort (35). The authors hypothesized that loss-of-function mutations in this gene could result in defective polyploidization of extravillous trophoblast, leading to loss of cytotrophoblast invasion. More work is needed to uncover the molecular signals governing cytotrophoblast invasion early in placentation, defects in which may underlie the early stages of preeclampsia. The lack of a naturally occurring animal model for preeclampsia and lack of access to human placental samples from early gestation have greatly limited research in this area.

VEGF: vascular endothelial growth factor


PlGF: placental growth factor

MATERNAL ENDOTHELIAL DYSFUNCTION Although preeclampsia appears to begin in the placenta, the target organ is the maternal endothelium. The clinical manifestations of preeclampsia reflect widespread endothelial dysfunction, resulting in vasoconstriction and end-organ ischemia. Incubation of endothelial cells with serum from women with preeclampsia results in endothelial dysfunction; hence, it has been hypothesized that circulating factors, probably originating in the placenta, are responsible for the manifestations of the disease (36). Dozens of serum markers of endothelial activation and endothelial dysfunction are deranged in women with preeclampsia, including von Willebrand antigen, cellular fibronectin, soluble tissue factor, soluble Eselectin, platelet-derived growth factor, and endothelin. There is evidence of oxidative 66

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stress and platelet activation (37). Inflammation is often present; for example, neutrophil infiltration is observed in the vascular smooth muscle of subcutaneous fat, with increased vascular smooth muscle expression of IL-8 and intercellular adhesion molecule1 (ICAM-1) (38). Several of these aberrations occur well before the onset of symptoms, supporting the central role of endothelial dysfunction in the pathogenesis of preeclampsia.

Hemodynamic Changes The decreases in peripheral vascular resistance and arterial blood pressure that occur during normal pregnancy are absent or reversed in preeclampsia. Systemic vascular resistance is high and cardiac output is low owing to widespread vasoconstriction. Interestingly, some have suggested that patients destined to develop preeclampsia start out with a hyperdynamic circulation during the preclinical stage and cross over to the vasoconstricted stage during the hypertensive phase (39). There is exaggerated sensitivity to vasopressors such as angiotensin II and norepinephrine (36). Women who go on to develop preeclampsia have impaired endothelium-dependent vasorelaxation (40) and subtle increases in blood pressure and pulse pressure (41) prior to onset of overt hypertension and proteinuria, suggesting that changes in endothelial function are present early in the course of the disease.

Renal Pathology The most characteristic pathologic changes in preeclampsia are seen in the kidney. In 1959, Spargo et al. coined the term glomerular endotheliosis to describe ultrastructural changes in renal glomeruli, including generalized swelling and vacuolization of the endothelial cells and loss of the capillary space (Figure 2a–c). There are deposits of fibrin within and under the endothelial cells, and electron microscopy shows loss of glomerular endothelial fenestrae. The primary injury appears to be to the endothelial cells; the


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a

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Figure 2 Glomerular endotheliosis (from Reference 98 with permission). All light micrographs taken at identical original magnification of 40×. (a) Normal human glomerulus, H & E. (b) Human preeclamptic glomerulus, H & E. Patient is a 33-year-old woman with twin gestation and severe preeclampsia at 26 weeks gestation with urine protein/creatinine ratio of 26 at the time of biopsy. (c) Electron microscopy of glomerulus of same patient. Note occlusion of capillary lumen with cytoplasm and expansion of subendothelial space with electron-dense material (asterisks). Podocyte cytoplasm shows protein resorption droplets (arrow) and relatively intact foot processes (arrow). Original magnification 1500×. (d ) Control rat glomerulus, H & E. Note normal cellularity and open capillary loops. (e) Glomerulus of rat treated with soluble fms-like tyrosine kinase-1 (sFlt-1), H & E. Note occlusion of capillary loops with minimal increase in cellularity. ( f ) Electron microscopy of sFlt-1 treated rat. Note occlusion of capillary loops by cytoplasm (asterisk) with relative preservation of podocyte foot processes (arrows). Original magnification 2500×.

podocyte foot processes are relatively intact early in disease, a finding atypical of other nephrotic diseases. Although glomerular endotheliosis was once considered pathognomonic for preeclampsia, recent studies have shown that mild glomerular endotheliosis also occurs in pregnancy without preeclampsia, especially in gestational hypertension (42). This suggests the endothelial dysfunction of preeclampsia may be an exaggeration of a process present near term in many normal pregnancies.

Cerebral Edema Cerebral edema and intracerebral parenchymal hemorrhage are common autopsy findings in women who died from eclampsia. The

presence of cerebral edema in eclampsia correlates with markers of endothelial damage but not the severity of hypertension (43), suggesting the edema is secondary to endothelial dysfunction rather than a direct result of blood pressure elevation. Findings on head CT and MRI are similar to those seen in hypertensive encephalopathy, with vasogenic cerebral edema and infarctions in the subcortical white matter and adjacent gray matter, predominantly in the parietal and occipital lobes (14). A syndrome that includes these characteristic MRI changes, along with headache, seizures, altered mental status, and hypertension, has been described in patients with acute hypertensive encephalopathy in the setting of renal disease, eclampsia, or immunosuppression (44). This syndrome, termed reversible


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posterior leukoencephalopathy, has subsequently been associated with the use of antiangiogenic agents for cancer therapy (45). This association supports the involvement of innate antiangiogenic factors in the pathophysiology of preeclampsia/eclampsia, as detailed in the next section.

sFlt1: soluble fms-like tyrosine kinase-1

ALTERATIONS IN ANGIOGENIC FACTORS


Recent work suggests that changes in circulating angiogenic factors play a key role in the pathogenesis of preeclampsia. Increased expression of soluble fms-like tyrosine kinase-1 (sFlt1), associated with decreased PlGF and VEGF signaling, were the first abnormalities described (46, 47). sFlt1 is a truncated splice variant of the membrane-bound VEGF receptor Flt1, also called VEGFR1. sFlt1 consists of the extracellular ligand-binding domain without the transmembrane and

intracellular signaling domains. Hence, sFlt1 is secreted rather than bound to the cell surface, and it has biological activity as an antagonist to both VEGF and PlGF, binding them in the circulation and preventing interaction with their endogenous receptors (48) (Figure 3). Placental expression of soluble Flt1 is increased in preeclampsia and is associated with a marked increase in maternal circulating sFlt1 (46). Several investigators have confirmed that the increase in maternal circulating sFlt1 precedes the onset of clinical disease (49–52) and is correlated with disease severity (51, 53). In vitro effects of sFlt1 include vasoconstriction and endothelial dysfunction. Exogenous sFlt1 administered to pregnant rats produces a syndrome resembling preeclampsia, including hypertension, proteinuria, and glomerular endotheliosis (46) (Figure 2d–f ). Thus, sFlt1 may be a key part of the mechanism linking the placenta with maternal endothelial dysfunction.

Figure 3 sFlt1 and soluble endoglin (sEng) cause endothelial dysfunction by antagonizing VEGF and TGF-β1 signaling (from Reference 99 with permission). There is mounting evidence that VEGF and TGF-β1 are required to maintain endothelial health in several tissues, including the kidney and perhaps the placenta. During normal pregnancy, vascular homeostasis is maintained by physiological levels of VEGF and TGF-β1 signaling in the vasculature. In preeclampsia, excess placental secretion of sFlt1 and sEng (two endogenous circulating antiangiogenic proteins) inhibits VEGF and TGF-β1 signaling, respectively, in the vasculature. This results in endothelial cell dysfunction, including decreased prostacyclin and nitric oxide production, and release of procoagulant proteins. 68

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Derangements in other angiogenic molecules have also been observed. Maternal serum levels of endostatin, an inhibitor of angiogenesis, are elevated in preeclampsia (54). Soluble endoglin (sEng) is upregulated in preeclampsia in a pattern similar to that of sFlt1. sEng is a truncated form of endoglin (CD105), a cell surface receptor for TGF-β, which binds and antagonizes TGF-β. sEng amplifies the vascular damage mediated by sFlt1 in pregnant rats, inducing a severe preeclampsia-like syndrome with features of the HELLP syndrome (55). This effect may be mediated by interference with nitric oxide–mediated vasodilation (Figure 3). As with sFlt1, circulating sEng levels are elevated weeks prior to preeclampsia onset (56). The precise role of sEng in preeclampsia and its relationship with sFlt1 is currently being explored.

(62). This suggests that VEGF deficiency— induced by excess sFlt1—can produce the characteristic renal manifestations of preeclampsia. It is also interesting to note that women with a history of preeclampsia have a decreased risk of malignancy (18, 63), suggesting that the antiangiogenic milieu of preeclampsia may extend beyond pregnancy. The physiologic role of PlGF is less well understood than that of VEGF, but PlGF appears to stimulate angiogenesis under conditions of ischemia, inflammation, and wound healing (64) and may contribute to atherosclerosis (65). Blockade of both VEGF and PlGF is required to produce preeclampsialike changes in pregnant rats (46), signifying that PlGF blockade may be important in the pathogenesis of sFlt1-induced endothelial dysfunction.

VEGF Signaling and Endothelial Cell Health

Angiogenic Signals in Placental Vascular Development

Circumstantial evidence supports the hypothesis that interference with VEGF/PlGF signaling could mediate endothelial dysfunction in preeclampsia. VEGF is important in the stabilization of endothelial cells in mature blood vessels. VEGF is particularly important in the health of the fenestrated and sinusoidal endothelium found in the renal glomerulus, brain, and liver (57)—organs severely affected in preeclampsia. VEGF is highly expressed by glomerular podocytes, and VEGF receptors are present on glomerular endothelial cells (58). Anti-VEGF therapies given to adult animals cause glomerular endothelial damage with proteinuria (59, 60). In a podocytespecific VEGF knockout mouse, heterozygosity for VEGF-A resulted in renal disease characterized by proteinuria and glomerular endotheliosis (61). The most striking experimental illustration of the effect of VEGF antagonism in humans comes from antiangiogenesis cancer trials, where anti-VEGF antibodies produce proteinuria, hypertension, and loss of glomerular endothelial fenestrae

Angiogenic factors are likely to be important in the regulation of placental vasculogenesis. VEGF ligands and receptors are highly expressed by placental tissue in the first trimester. sFlt1 decreases cytotrophoblast invasiveness in vitro (33). Circulating sFlt1 levels are relatively low early in pregnancy and begin to rise in the third trimester. This may reflect a physiologic antiangiogenic shift in the placental milieu toward the end of pregnancy, corresponding to completion of the vasculogenic phase of placental growth. It is intuitive to hypothesize that placental vascular development might be regulated by a local balance between pro- and antiangiogenic factors and that alterations in these pathways in early gestation could contribute to inadequate cytotrophoblast invasion in preeclampsia. By the third trimester, excess placental sFlt1 is detectable in the maternal circulation, producing end-organ effects. In this case, placental ischemia may not be causative but rather reflective of this derangement of angiogenic balance.


sEng: soluble endoglin

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Mechanistic Insights into Clinical Risk Factors


The discovery of the importance of sFlt1 has provided insight into certain preeclampsia risk factors. Higher sFlt1 levels have been noted in first versus second pregnancies (66), twin versus singleton pregnancies (67), and pregnancies with fetuses having trisomy 13 (68)— all established risk factors for preeclampsia. Conversely, decreased levels of sFlt1 in smokers (69) may explain the protective effect of smoking in preeclampsia. This effect may be mediated by carbon monoxide, a byproduct of cigarette smoking, which diminishes VEGFinduced sFlt1 and sEng release from cultured endothelial cells (70).

Preeclampsia and IUGR: Shared Clinical and Pathophysiologic Features It has long been recognized that preeclampsia and intrauterine growth restriction (IUGR) share many common clinical and pathologic features. IUGR is a common complication of preeclampsia, and abnormal uterine blood flow by Doppler ultrasound in early pregnancy is associated with an increased risk for both disorders. Why some women with placental insufficiency manifest the systemic syndrome of preeclampsia, while others have small-for-gestational-age babies without these maternal symptoms, is unknown. With regard to angiogenic factors, there appears to be some overlap between the two syndromes. Some (71–73) but not all (49, 74) studies report that women with IUGR but without preeclampsia have increased circulating sFlt1 and sEng and decreased PlGF. Alterations in angiogenic factors in IUGR without preeclampsia, when detected, are less pronounced than in preeclampsia. Given the pathologic and clinical overlap between IUGR and preeclampsia, it is our belief that the two conditions probably share common pathophysiologic underpinnings, at least at the level of insufficient placental vascular de70

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velopment. Variability in clinical phenotype is probably attributable to individual environmental and genetic differences that alter the maternal response to the placental disease.

OTHER PIECES OF THE PREECLAMPSIA PUZZLE The Renin-Angiotensin-Aldosterone System Women with preeclampsia have increased vascular responsiveness to angiotensin II and other vasoconstrictive agents. However, plasma renin levels are suppressed relative to normal pregnancy as a secondary response to systemic vasoconstriction and hypertension. Wallukat et al. (75) identified agonistic angiotensin II type 1 (AT1) receptor autoantibodies in women with preeclampsia. They hypothesized that these antibodies, which activate the AT1 receptor, may account for the increased angiotensin II sensitivity of preeclampsia. The same investigators later showed that these AT1 receptor autoantibodies, like angiotensin II itself, stimulate endothelial cells to produce tissue factor, an early marker of endothelial dysfunction. Xia et al. (76) found that AT1 receptor autoantibodies decreased invasiveness of immortalized human trophoblasts in an in vitro invasion assay, suggesting that these autoantibodies might contribute to defective placental pseudovasculogenesis as well. AT1 receptor autoantibodies are not limited to pregnancy; they also appear to be increased in malignant renovascular hypertension and vascular rejection in nonpregnancy (77). Work by Abdalla et al. (78) has suggested that heterodimerization of AT1 receptors with bradykinin 2 receptors may contribute to angiotensin II hypersensitivity in preeclampsia. This work remains to be validated in other studies.

Oxidative Stress and Inflammation Oxidative stress—i.e., the presence of reactive oxygen species in excess of antioxidant


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buffering capacity—is a prominent feature of preeclampsia. It has been hypothesized that in preeclampsia, placental oxidative stress is transferred to the systemic circulation, resulting in oxidative damage to the maternal vascular endothelium. However, the absence of any clinical benefit of antioxidant supplementation for the prevention of preeclampsia suggests that oxidative stress is probably a secondary phenomenon in preeclampsia and not a promising therapeutic target (79). Circulating placental cytotrophoblast debris and the accompanying inflammation have also been proposed as a pathogenic mechanism to explain the maternal endothelial dysfunction, but causal evidence for this hypothesis is still lacking (80).

important role in immune tolerance required for normal placental development, have been recently noted to induce angiogenic factors and vascular remodeling (84). Moreover, genetic studies suggest that the susceptibility to preeclampsia may be influenced by polymorphic human leukocyte antigen C (HLA-C) ligands and the killer immunoglobulin receptors (KIRs) present on NK cells (85). These data suggest that decidual NK cells secrete cytokines and angiogenic factors that play an important role during normal placental vascular remodeling and differentiation, and that alterations in NK cell signaling may mediate abnormal placentation noted in preeclampsia.

CLINICAL IMPLICATIONS OF RECENT ADVANCES

Immunologic Intolerance Immune maladaption remains an intriguing but unproven theory of the pathogenesis of preeclampsia. Normal placentation requires the development of immune tolerance between the fetus and the mother. Preeclampsia occurs more often in first pregnancies, after a change in paternity (81), or with long interpregnancy interval (3). Prolonged maternal exposure to paternal ejaculate appears to be associated with a decreased risk of preeclampsia. For example, women using contraceptive methods that reduce exposure to sperm have increased preeclampsia incidence (82). Women impregnated by intracytoplasmic sperm injection (ICSI) in which sperm were surgically obtained (i.e., the woman was never exposed to partner’s sperm in intercourse) had a threefold increased risk of preeclampsia compared to ICSI cases where sperm were obtained by ejaculation (i.e., the woman was likely to have prior exposure to paternal ejaculate via intercourse) (83). These observations suggest preeclampsia may involve an abnormal maternal immune response to novel paternally derived fetal antigens. Natural killer (NK) cells at the maternal/ fetal interface, which are thought to play an

Screening and Prediction Although there is not yet any definitive therapeutic or preventive strategy for preeclampsia, clinical experience suggests that early detection, monitoring, and supportive care are beneficial to the patient and the fetus. Reliable prediction of preeclampsia would allow closer prenatal monitoring, early diagnosis, and timely intervention with steroids to enhance fetal lung maturity, magnesium for seizure prophylaxis, antihypertensive medications, bed rest, and—when indicated— expeditious delivery. Furthermore, a robust biomarker for preeclampsia would enable targeted studies of therapies and preventive strategies for preeclampsia, including existing (e.g., antiplatelet agents), controversial (calcium, antioxidants), and novel approaches. However, no screening test has yet proven accurate enough for widespread clinical use (86). Alterations in circulating levels of angiogenic factors occur weeks prior to the onset of preeclampsia and are promising biomarkers for screening and/or diagnosis. Significant elevations in maternal sFlt1 and sEng are observed from mid-gestation onward


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(49, 87) and appear to rise 5–8 weeks prior to preeclampsia onset (51, 56). Maternal sFlt1 levels are particularly elevated in severe preeclampsia, early-onset preeclampsia, and preeclampsia complicated by a small-forgestational-age baby (51, 88). Serum levels of PlGF are lower in women who go on to develop preeclampsia from the first (89) or early second (51, 90, 91) trimester. The ratio of sFlt1 to PlGF has been proposed as an index of antiangiogenic activity that reflects alterations in both biomarkers (92) and is a better predictor of preeclampsia than either measure alone (56). Because PlGF is small enough to pass into the urine, changes in urinary PlGF may be a potential marker for preeclampsia. Urinary levels of PlGF are significantly lower in women who develop preeclampsia from the late second trimester (92) and may prove useful in screening and diagnosis of preeclampsia, especially in early-onset and severe disease (93). SEng is also elevated in the maternal circulation prior to preeclampsia onset, with gestational patterns similar to those of sFlt1. From the late second and early third trimester, elevations in both sEng and the sFlt1:PlGF ratio (but not either biomarker alone) are associated with very high risk (odds ratio >30) for the development of preterm preeclampsia (56). The timing, source (i.e., serum versus urinary), and combination of biomarkers and other tests that will prove most predictive of preeclampsia and its sequelae are now being explored in prospective studies. For example, a recent cohort study found that the combination of abnormal uterine artery Doppler and low serum PlGF in the second trimester was strongly associated with both early-onset and severe preeclampsia, with odds ratios of 35–45 (94). Other work suggests that rapid changes in angiogenic factor levels with advancing gestation may be more predictive of preeclampsia than levels at any single point in gestation (95, 96). It is likely that these discoveries will enhance our ability to identify women at high risk much earlier in gestation, which


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would improve clinical management and open up possibilities for early intervention.

Novel Treatment Strategies Currently, the only definitive treatment for preeclampsia is delivery of the fetus and placenta. In the late second and early third trimester, preeclampsia requiring delivery to preserve the health of the mother can result in significant neonatal morbidity and mortality due to prematurity. The identification of sFlt1 and sEng as a key pathogenic link between placental pathology and maternal endothelial damage provides hope that these biomarkers may also be effective therapeutic targets. Potential therapies may be directed at restoring normal angiogenic balance in the maternal circulation—that is, the relative biologic activity of proangiogenic factors such as VEGF and PlGF relative to antiangiogenic factors such as sFlt1 and sEng. For example, VEGF121 was recently shown to diminish hypertension and proteinuria in a rat model of sFlt1induced preeclampsia, without apparent harm to the fetus (96a). Such therapies may transform the way preeclampsia is treated; an intervention that allows clinicians to safely postpone delivery for even a few weeks could have a tremendous impact on neonatal morbidity and mortality in select cases. Although much more work is needed, we soon may see real improvements in the management of this ancient syndrome.

SUMMARY AND FUTURE DIRECTIONS The past five years have provided exciting advances in our understanding of the pathogenesis of preeclampsia. Although the initiating events in preeclampsia are still not known, recent work suggests that excess circulating antiangiogenic factors (sFlt1 and sEng) may be a pathophysiologic link between the placental disease and the systemic maternal manifestations. The implications for the management of preeclampsia may be profound. More

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work is needed to further define the regulation of placental vascular development and expression of these factors in normal pregnancy

and in preeclampsia, and the mechanisms responsible for variability in the maternal response.

DISCLOSURE STATEMENT S.E.M. and S.A.K are listed as coinventors on provisional patents filed by the Beth Israel Deaconess Medical Center for the diagnosis and therapy of preeclampsia. S.A.K is a consultant to Beckman Coulter, Johnson & Johnson, and Abbott Diagnostics.


ACKNOWLEDGMENTS S.A.K. is supported by NIH grants (DK065997 and HL079594). S.E.M. is supported by the Partnership for Cures, Charles E. Culpeper Scholarship in Medical Sciences.

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92. Levine RJ, Thadhani R, Qian C, et al. 2005. Urinary placental growth factor and risk of preeclampsia. JAMA 293:77–85 93. Buhimschi CS, Norwitz ER, Funai E, et al. 2005. Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia. Am. J. Obstet. Gynecol. 192:734–41 94. Espinoza J, Romero R, Nien JK, et al. 2007. Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor. Am. J. Obstet. Gynecol. 196:326 e1–13 95. Vatten LJ, Eskild A, Nilsen TI, et al. 2007. Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia. Am. J. Obstet. Gynecol. 196:239 e1–6 96. Moore Simas T, Solitro M, Nadkarni S, et al. 2007. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am. J. Obstet. Gynecol. 197:244.e1–244.e8 96a. Li Z, Zhang Y, Ying Ma J, et al. 2007. Recombinant vascular endothial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 50:686–92 97. Lam C, Lim KH, Karumanchi SA. 2005. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46:1077–85 98. Karumanchi SA, Maynard SE, Stillman IE, et al. 2005. Preeclampsia: a renal perspective. Kidney Int. 67:2101–13 99. Karumanchi SA, Epstein FH. 2007. Placental ischemia and soluble fms-like tyrosine kinase 1—cause or consequence of preeclampisa? Kidney Int. 71(10):959–61


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Annual Review of Medicine


Contents

Volume 59, 2008

The FDA Critical Path Initiative and Its Influence on New Drug Development Janet Woodcock and Raymond Woosley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1 Reversing Advanced Heart Failure by Targeting Ca2+ Cycling David M. Kaye, Masahiko Hoshijima, and Kenneth R. Chien p p p p p p p p p p p p p p p p p p p p p p p p 13 Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis Ulla Hedner and Mirella Ezban p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29 Therapy of Marfan Syndrome Daniel P. Judge and Harry C. Dietz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 43 Preeclampsia and Angiogenic Imbalance Sharon Maynard, Franklin H. Epstein, and S. Ananth Karumanchi p p p p p p p p p p p p p p p p p 61 Management of Lipids in the Prevention of Cardiovascular Events Helene Glassberg and Daniel J. Rader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 79 Genetic Susceptibility to Type 2 Diabetes and Implications for Antidiabetic Therapy Allan F. Moore and Jose C. Florez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 95 Array-Based DNA Diagnostics: Let the Revolution Begin Arthur L. Beaudet and John W. Belmont p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p113 Inherited Mitochondrial Diseases of DNA Replication William C. Copeland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p131 Childhood Obesity: Adrift in the “Limbic Triangle” Michele L. Mietus-Snyder and Robert H. Lustig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147 Expanded Newborn Screening: Implications for Genomic Medicine Linda L. McCabe and Edward R.B. McCabe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p163 Is Human Hibernation Possible? Cheng Chi Lee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p177 Advance Directives Linda L. Emanuel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p187 v

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Genetic Determinants of Aggressive Breast Cancer Alejandra C. Ventura and Sofia D. Merajver p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199 A Role for JAK2 Mutations in Myeloproliferative Diseases Kelly J. Morgan and D. Gary Gilliland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p213 Appropriate Use of Cervical Cancer Vaccine Gregory D. Zimet, Marcia L. Shew, and Jessica A. Kahn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p223 A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkin’s Lymphoma Arturo Molina p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p237


Nanotechnology and Cancer James R. Heath and Mark E. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p251 Cancer Epigenetics: Modifications, Screening, and Therapy Einav Nili Gal-Yam, Yoshimasa Saito, Gerda Egger, and Peter A. Jones p p p p p p p p p p p p267 T Cells and NKT Cells in the Pathogenesis of Asthma Everett H. Meyer, Rosemarie H. DeKruyff, and Dale T. Umetsu p p p p p p p p p p p p p p p p p p p p281 Complement Regulatory Genes and Hemolytic Uremic Syndromes David Kavanagh, Anna Richards, and John Atkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p293 Mesenchymal Stem Cells in Acute Kidney Injury Benjamin D. Humphreys and Joseph V. Bonventre p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p311 Asthma Genetics: From Linear to Multifactorial Approaches Stefano Guerra and Fernando D. Martinez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p327 The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in Human Disease Stavros Garantziotis, John W. Hollingsworth, Aimee K. Zaas, and David A. Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p343 Advances in Antifungal Therapy Carole A. Sable, Kim M. Strohmaier, and Jeffrey A. Chodakewitz p p p p p p p p p p p p p p p p p p361 Herpes Simplex: Insights on Pathogenesis and Possible Vaccines David M. Koelle and Lawrence Corey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381 Medical Management of Influenza Infection Anne Moscona p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p397 Bacterial and Fungal Biofilm Infections A. Simon Lynch and Gregory T. Robertson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p415 EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story Lecia V. Sequist and Thomas J. Lynch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p429 Adaptive Treatment Strategies in Chronic Disease Philip W. Lavori and Ree Dawson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443 vi

Contents

AR334-FM

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Antiretroviral Drug–Based Microbicides to Prevent HIV-1 Sexual Transmission Per Johan Klasse, Robin Shattock, and John P. Moore p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p455 The Challenge of Hepatitis C in the HIV-Infected Person David L. Thomas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p473 Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection Luc Geeraert, Günter Kraus, and Roger J. Pomerantz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p487


Advancements in the Treatment of Epilepsy B.A. Leeman and A.J. Cole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p503 Indexes Cumulative Index of Contributing Authors, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p525 Cumulative Index of Chapter Titles, Volumes 55–59 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p529 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://med.annualreviews.org/errata.shtml

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Management of Lipids in the Prevention of Cardiovascular Events Helene Glassberg1 and Daniel J. Rader2 1

Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; email: [email protected]

2

Cardiovascular Institute; Institute for Diabetes, Obesity and Metabolism; and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; email: [email protected]

Annu. Rev. Med. 2008. 59:79–94

Key Words

First published online as a Review in Advance on October 15, 2007

cholesterol, triglycerides, high-density lipoproteins, cardiovascular risk

The Annual Review of Medicine is online at http://med.annualreviews.org This article’s doi: 10.1146/annurev.med.59.121206.112237 c 2008 by Annual Reviews. Copyright All rights reserved 0066-4219/08/0218-0079$20.00

Abstract Lipid-modifying therapy has been proven to significantly reduce cardiovascular events and total mortality. Most of the data have come from statin trials. Statin therapy is generally well-tolerated and safe, and for patients who are at higher than average risk of cardiovascular disease, the benefit of lipid-modifying therapy far exceeds the risk. Careful risk assessment is a critical component of effective lipidmodifying therapy. In the foreseeable future, low-density lipoprotein cholesterol (LDL-C) will remain the primary therapeutic target, and combination therapy is likely to become the norm. The major questions are how low to treat and how to achieve increasingly aggressive targets in lipid-lowering therapy. Many patients on LDL-lowering therapy continue to have abnormalities of the triglyceride–highdensity lipoprotein (TG-HDL) axis, so additional drug therapy is often considered for such patients. In this review, we briefly discuss new developments in cardiovascular risk assessment, then discuss recent developments in treatment to reduce LDL, and finally discuss current concepts regarding therapy targeting the TG-HDL axis.

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INTRODUCTION CAD: coronary artery disease


HDL-C: high-density lipoprotein cholesterol TG-HDL axis: balance of triglycerides and HDL-C. Even with successful LDL-lowering therapy, many patients have residual high triglyceride, low HDL-C, or both CHD: coronary heart disease FRS: Framingham Risk Score

Dyslipidemia is an important risk factor for coronary artery disease (CAD) and other atherosclerotic vascular disease. Elevated levels of atherogenic lipoproteins [low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL)] and reduced levels of antiatherogenic lipoproteins [high-density lipoproteins (HDL)] are targets for therapeutic intervention. It has been clearly demonstrated that lowering LDL cholesterol (LDLC) levels with diet and drugs significantly reduces the risk of cardiovascular events and total mortality, and guidelines for treatment to reduce LDL-C have become increasingly aggressive, particularly in high-risk patients. Evidence supporting treatment to lower triglycerides or raise HDL-C levels is much less abundant, and formal guidelines are nonexistent. The decision to employ drug therapy targeted to the “TG-HDL axis” is left to the clinical judgment of the physician. Accurate risk assessment is imperative so that patients receive an appropriate level of lipid-modifying drug therapy. In this review, we focus first on cardiovascular risk assessment as a critical determinant of the intensity of lipid-modifying therapy. We then discuss recent developments in treatment to reduce LDL and other atherogenic lipoproteins. Finally, we discuss current concepts regarding utilization of therapy that targets the TG-HDL axis.

SCREENING FOR ALL ADULTS The Adult Treatment Panel (ATP) III guidelines of the National Cholesterol Education Program (NCEP) of the National Heart Lung and Blood Institute (1) recommended that all adults over age 20 undergo a fasting full lipid panel to evaluate triglycerides, total cholesterol, HDL-C, and calculated LDL-C. [The LDL-C is calculated from the other lipid values using the following equation: LDL-C = total cholesterol – (triglycerides/5) – HDLC.] The guidelines also recommended the 80

Glassberg

·

Rader

clinical use of the “non-HDL-C” level as a secondary target of therapy in patients with fasting triglyceride levels >200 mg/dl. The guidelines strongly emphasize risk assessment and stratification as a guide to intensity of lipid-modifying drug therapy.

CARDIOVASCULAR RISK ASSESSMENT All decisions regarding lipid management are conditioned by the level of cardiovascular risk, including short-term, 10-year, and lifetime risk. Decisions such as whether to initiate lipid-modifying drug therapy, what target to set for the LDL-C level, and whether to employ combination therapy targeted to the TGHDL axis are all influenced by the clinician’s assessment of cardiovascular risk. The key categories of cardiovascular risk, as established by the NCEP ATPIII guidelines (1) and further modified by a subsequent update (2), are as follows: 1. Recent acute coronary syndrome 2. Pre-existing stable atherosclerotic cardiovascular disease 3. Diabetes mellitus, considered a “coronary heart disease (CHD) risk equivalent” condition 4. Absolute 10-year risk of a cardiovascular event >20% as determined by the Framingham Risk Score (FRS), also a CHD risk equivalent condition 5. Absolute FRS 10-year risk of 10%– 20%, considered “moderate risk” 6. Absolute FRS 10-year risk of 135 mg/dl. Treatment with simvastatin 40 mg was associated with a highly significant 24% reduction in major coronary events, 25% reduction in stroke, and 13% reduction in total mortality. Benefit of simvastatin therapy was evident regardless of baseline cholesterol, even among the group with LDL-C

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Biotechnology Annual Review, Volume 14

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Annual Review of Nano Research, Volume 3

Annual Review of Immunology Volume 23 2005

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