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
NHLBI Staff:
- 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
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