NHLBI Working Group
Future Directions for Hypertension Research

Executive Summary

I. Introduction and Charge

Hypertension is a major public health problem worldwide, affecting over 50 million individuals in the United States alone. It is a major risk factor for target organ damage resulting in coronary artery disease, heart failure, stroke, and kidney disease. Despite increased efforts to prevent, treat, and control hypertension and its sequelae, the prevalence of hypertension in the United States has not decreased. The pathogenesis of high blood pressure remains unclear, and consequently treatment is currently based on using drugs with an emphasis on reducing the elevated blood pressure rather than treating its causative factors.

A major goal of basic hypertension research is to identify the underlying biological pathways and mechanisms responsible for abnormalities in blood pressure control, related risk factors, co-morbidities, and susceptibility to target organ damage. Genetic studies over the past decade have demonstrated the enormous complexity involved in understanding the causes of high blood pressure. It has become clear that no single approach will answer the key questions related to the biological mechanisms underlying high blood pressure. Hence, interdisciplinary research models emphasizing all levels of inquiry, from the gene to the intact organism, are now required to yield the important and much needed data on the causes of high blood pressure and target organ damage.

A Working Group on Future Directions for Hypertension Research was convened on May 24-25, 2004 to assist the National Heart, Lung, and Blood Institute in identifying and prioritizing basic biomedical research goals, which could include animal and human studies, in the areas of normal blood pressure control, hypertension mechanisms, and approaches to understand and prevent target organ damage. Clinical trials and epidemiological observational studies were not encompassed within the charge to the working group. Working group members were encouraged to identify research areas that through Institute-initiated activities could provide over the next decade a significant stimulus for research on the pathogenesis and treatment of high blood pressure and on susceptibility to target organ damage.

II. Current Challenges Facing Hypertension Research

A major challenge in the field of hypertension is to identify the key determinants of long-term blood pressure control and to evaluate how these critical pathways can best be modified to reduce blood pressure and disease risk. Decades of work in diverse areas have identified a large number of factors that are altered in the setting of hypertension. Over the past 10 years, genetic approaches have made an enormous contribution to understanding the pathogenesis of high blood pressure by allowing researchers to view hypertension from a new perspective. As more genes and intermediate phenotypes are identified, it is becoming increasingly clear that interdisciplinary approaches will be required for continued progress in understanding the etiology of this disease.

The genetic approach consequently has the capacity to establish true causal relationships between specific genes and intermediate biological pathways that lead to the trait of interest, such as hypertension. The opportunities to utilize genetics have been dramatically improved with the completion of the human, mouse, and rat genome sequences and by development of the haplotype map.

The scientific community is now challenged by the need to form teams of researchers who collaborate in the design of studies that simultaneously draw upon expertise in the fields of genomics, proteomics, bioinformatics, statistical genetics, cellular and integrative physiology, mathematics, and computational biology. It will be a great challenge to bring these diverse scientific disciplines together to carry out large scale genomic and proteomic studies in both experimental animal models and human populations.

An equally important challenge in hypertension research remains the goal of reducing the devastating target organ damage seen in the brain, kidney, systemic vasculature, and heart as a consequence of uncontrolled hypertension. It has been generally difficult to determine the extent to which changes in these systems have been a cause or result of hypertension, and it is now important to make efforts to separate the cause and effect relationships.

III. Possible Future Programmatic Activities in Hypertension

Summarized below are ideas that emerged from discussions of the working group members. Consideration was given to both research areas of importance and to how the research areas should be organized. It will be important to study high blood pressure in combination with other cardiovascular diseases. Studying hypertension in isolation of other diseases, such as dyslipidemias, arteriosclerosis, non-insulin dependent diabetes, and the metabolic syndrome, may hinder our ability to make new breakthroughs in understanding the origins of the disease.

Examples of hypertension research areas that could benefit from an interdisciplinary research approach are briefly described below:

Continue Genotypic Characterizations of Hypertension

The effort to attach function and disease susceptibility to the genomic backbone has barely begun, and any serious effort in the future to understand hypertension must include genetic and genomic approaches. Consequently, efforts to identify the genetic polymorphisms that are involved in the biological pathways culminating in high blood pressure must continue.

The following related areas should also be stimulated: [1] In addition to the need for more extensive phenotyping of humans and animal models of high blood pressure, it will be necessary to find ways of stratifying the population to reduce genetic and environmental heterogeneity. [2] Research should be stimulated to identify functional genetic polymorphisms that affect the response to antihypertensive medications. [3] Due to the continued high demand and need for the rat model system in cardiovascular and pulmonary research, improvement of gene knockout technologies in this species should be encouraged to bring genetic manipulation of the rat on a par with that in the mouse.

Develop Novel Mathematical Modeling and Quantitative Biological Approaches

It is increasingly apparent among investigators in many biomedical disciplines that the understanding of the integration of biological systems has just begun. There is a need for investigators to re-emphasize that hypertension research requires more quantitative approaches and modeling of cardiovascular system dynamics. A fully integrative mathematical approach is essential for the complete analysis of currently available data. Research data needs to be analyzed from long-term, continuous but minimally invasive observations of cardiovascular variables in humans and animal models under a variety of behavioral and environmental conditions. Such quantitative knowledge and mathematical modeling will be critical to incorporating and understanding the complex interactions of the hundreds of gene effects that certainly will be found to influence blood pressure regulation.

Systems biology was discussed as one possible interdisciplinary approach to studying disorders of blood pressure regulation. Systems biology is the delineation of the elements in a biological system and the analysis of their interactions after genetic or environmental perturbations. The goal of systems biology is to explain the system's emergent properties, which may be defined as phenotypic traits that are absent when elements of a system are studied in isolation, but that are only present when multiple elements within a system interact. Systems are generally viewed as operating in the context of a cell, organ, or organism, and systems biology research should be viewed as hypothesis-driven, quantitative, integrative, and iterative.

A key aspect of systems biology is viewing biology as an informational science. There are two general types of biological information: the digital information of the genome and environmental cues that interact directly or indirectly with the digital genomic information. The systems biology approach generally proceeds in the following fashion:

A biological system is chosen, and all preexisting relevant information is integrated into a model that may be descriptive, graphical, or mathematical. A global analysis of the systems elements is carried out. Generally, this analysis begins with a genome sequence. Genes, their corresponding proteins, and transcription factor binding sites may be catalogued, predicted computationally, or experimentally identified. The system is then perturbed genetically or environmentally and global data sets are collected from as many different data types as possible. Genetic perturbations include overexpression, underexpression, or knockouts. Environmental perturbations may include the introduction of substrates that activate metabolic pathways, and hormones that trigger signal transduction pathways. The different data types must be integrated and then compared against the initial model. The ultimate objective is to move toward an accurate mathematical model of the emergent properties under study.

Establish Biological Mechanisms for Factors Known to Associate with Hypertension

More effort needs to be directed toward understanding how factors already known to affect blood pressure actually work on a physiological level. The genetic, environmental, and dietary factors that alter the critical set-point for sodium and fluid excretion must be determined. Due to its complex, multifactorial, and multigenetic nature, the pathogenesis of hypertension follows a slow, evolving process. Little is known about the control of blood pressure in humans and animal models over extended periods of time ranging from months to years. What has been understood for decades is that the kidney and the central nervous system are involved in a complex interaction that is key to the overall homeostasis of blood pressure. Given the research approaches currently available to study central and peripheral neural function, advances related to the role of this system in essential hypertension should be strongly encouraged.

Numerous findings indicate that the nervous system invariably influences and often precipitates certain types of cardiovascular disease. Furthermore, the central nervous system offers largely unrecognized opportunities for the development of more effective treatments for cardiovascular disease, as well as for a better understanding of how behavioral stress may influence the activity of numerous areas of the brain, which can contribute to the hypertensive disease process. Recent advances in medical imaging technologies allow for non-invasive studies of the living human brain and the kidney that would now enable the interrelationship of the structure, function, and dysfunction of these two key organ systems to be clarified.

Identify Prehypertensive Phenotypes and Biomarkers

Results from epidemiological studies and animal research suggest that it may be possible to prevent or significantly delay many of the morbid events associated with hypertension if susceptible individuals can be identified early enough in life. Understanding early markers of prehypertension that establish a biological risk of developing hypertension and target organ damage is an important research area. Prehypertension is defined as systolic blood pressure between 120 and 139 mm Hg and a diastolic blood pressure between 80 and 89 mm Hg. Markers for early detection remain a challenge, and it will be necessary to make efforts to explore combinations of genotypic, biochemical, and physiological approaches to define and stratify the population at risk.

Understand Global Cardiovascular Risk Factor Clustering in Hypertension

Another important research area that requires investigation is an understanding of the biological mechanisms underlying cardiovascular risk factor clustering in high blood pressure. An extension of this research is the need to address the prevention and pharmacological management of the concomitant illnesses commonly observed in conjunction with high blood pressure, such as focal glomerular sclerosis and tubulointerstitial disease in the kidney, hyperlipidemias, atherosclerosis, coronary artery disease, insulin resistance, and stroke.

Closely associated with this area of investigation is furthering our understanding of obesity as a cause of hypertension and the associated metabolic abnormalities that lead to diabetes and further cardiovascular disease. The metabolic syndrome is now recognized not only as an insulin resistant state, but as a proinflammatory state as well. The adipocyte is a dynamic endocrine cell producing adipokines, such as tumor necrosis factor, leptin and interleukin-6. The effects of these adipokines on blood pressure, insulin action, and vascular inflammation, as well as their interaction with components of the renin-angiotensin system, need to be defined. To what extent these conditions share common genetic determinants also remains to be determined.

Several lines of research suggest that hypertension shares a number of common elements with atherosclerotic vascular disease. Vascular oxidative stress, such as through the superoxide anion, is a common feature of both high blood pressure and atherosclerosis. Adhesion and chemoattractant molecules are activated in hypertension as well as in atherosclerosis. Angiotensin II is a potent proinflammatory agent, a characteristic that is independent of its pressor properties. Hypertension as an inflammatory disorder is an intriguing hypothesis. Systolic, diastolic, pulse, and mean arterial pressure have been positively correlated with increasing levels of interleukin-6, an inflammatory marker in humans. The plasma level of C-reactive protein has been linked to the future development of hypertension. How cytokines contribute to the regulation of blood pressure needs to be explored.

Develop Novel Treatment Paradigms

Efforts to develop novel treatment paradigms should target the primary causes of high blood pressure, the cardiovascular risk factors that contribute to essential hypertension, and the behavioral obstacles that limit successful control of hypertension in clinical practice. Examples of novel treatment paradigms include transcription modulating drugs, gene based therapeutics, new inhibitors of enzymes within mitochondrial energy pathways, and advanced techniques for drug delivery and blood pressure measurement. Repair of target organ damage utilizing progenitor/stem cells should also be studied. How these cells might play a reparative role in tissues following hypertension-induced injury remains unexplored. Whether endogenous cells serve any significant repair function in the context of target organ damage needs to be examined. The ways in which hypertension itself affects these cells (e.g. hormonally, mechanically, or by oxidant-stress) will also be important to study in order to determine whether there might be a cell-protective category of potential pharmacological targets to reduce the morbidity of hypertension.

IV. Recommendation

The working group concluded that a new overall scientific approach to the problem of hypertension is needed if progress is to be made on the scientific areas summarized above. Working group members noted that the goal of a new program in hypertension research should be to examine how the individual parts and local events within a biological system contribute to the complex, multifactorial, emergent properties of the whole organism. Consequently, the working group members recommended that a program on the integrated biology of hypertension be established.

Working Group Members

Co-Chairs:

• Bradford C. Berk, M.D., Ph.D., Department of Medicine, University of Rochester Medical Center
• Allen W. Cowley, Ph.D., Department of Physiology, Medical College of Wisconsin

Members:

• Carlos M. Ferrario, MD, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine
• Leroy Hood, MD, Ph.D., Institute for Systems Biology
• Willa Hsueh, MD, David Geffen School of Medicine, University of California-Los Angeles
• Mark A. Kay, MD, Ph.D., Departments of Pediatrics and Genetics, Stanford University School of Medicine
• Theodore W. Kurtz, MD, Department of Laboratory Medicine, University of California, San Francisco
• Richard P. Lifton, MD, Ph.D., Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine
• Keith L. March, MD, Ph.D., Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine
• R. Clinton Webb, Ph.D., Department of Physiology, Medical College of Georgia

• Michael C. Lin, Ph.D., National Heart, Lung, and Blood Institute
• Paul A. Velletri, Ph.D., National Heart, Lung, and Blood Institute

Last updated: August 26,2004