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Researchers

Target Organ Damage in Hypertension

The National Heart Lung and Blood Institute convened a Working Group of investigators on June 24-25, 2008 in Bethesda, Maryland. Their objectives were to identify new research directions that elucidate the basic biophysical and biological mechanisms underlying organ damage in hypertension and that lead to development of preclinical and presymptomatic markers of organ damage to allow early treatment decisions with the goal of attenuating or preventing organ damage.

Discussion:

The Working Group discussed:

  • The pathological changes in the heart, kidney and brain that result from primary or essential hypertension and considered possible mechanisms that could initiate the vascular damage in each organ;
  • The possibility that inflammation and oxidative stress are common triggers in the pathological changes of organs exposed to elevated blood perfusion pressure, and the need to explore the role of specific inflammatory cell types and their mediators in initiating vascular damage;
  • How hypertension-induced changes in microvascular function and rarefaction, fibrosis and extracellular matrix remodeling might affect tissue perfusion and oxygenation, and thus, cause organ damage;
  • The need to understand genetic susceptibilities to organ damage and their interaction with environmental influences;
  • The need to identify and validate biomarkers that signal the early stages of organ damage and their utility in translational research.

A general consensus developed over the course of the meeting that research attention should be focused in two broad areas. Firstly, the need to develop animal models that accurately recapitulate the preclinical and clinical phases of human essential hypertension and associated organ damage. Secondly, the need to develop methodologies and minimally invasive techniques that can overcome existing barriers to mechanistic studies of hypertension associated organ damage in human subjects. For example, in vivo serial dynamic imaging could be used to track cellular and molecular events during the progression of hypertension, and to identify novel biomarkers that will help define mechanisms, assist in detecting preclinical disease, and improve the accuracy of risk stratification.

The working group also enumerated specific areas that have received inadequate attention including isolated or predominately systolic hypertension, hypertension in African Americans, and the role of sex hormones in the development of hypertension in perimenopausal women. The working group emphasized the need to gain further understanding of the role of age, sex, race and the environment on susceptibility to organ damage in hypertension.

Recommendations:

  • Support studies on the role of specific inflammatory cells (e.g., T lymphocytes, macrophages and antigen presenting cells) and their mediators in the initiation of vascular damage and its progression to organ damage.
    • Determine whether a unique aspect of the hypertensive state (e.g., increased pulse pressure) activates inflammatory signaling pathways
    • Determine the role of the thymus in hypertension-related organ damage
    • Determine the relative roles of the adaptive versus the innate immune response in organ damage
    • Determine  whether inflammation is related causally to hypertension and associated vascular disease
    • Determine  whether inflammatory molecules are not only markers but also mediators of the inflammatory process
    • Determine the relationship between inflammation and oxidative stress, and elucidate their reciprocally interacting pathways
  • Support mechanistic studies to determine how hypertension-associated vascular remodeling (e.g., rarefaction, extracellular matrix remodeling and fibrosis) affects:
    • Overall tissue perfusion and oxygenation
    • Local regulation of tissue blood flow
    • Tissue levels of oxidative stress
    • Organ function
  • Support studies of age-related changes in the aorta and other central vessels (e.g., carotid, femoral arteries, etc.) with respect to hemodynamics in experimental models and human subjects.
    • Determine the molecular changes leading to conduit artery stiffening
    • Identify new tools/techniques needed to investigate the pulsatile hemodynamics in humans and models of human hypertensive disease
  • Support studies focused on the molecular mechanisms induced by oxidative stress to trigger damage to the vasculature of organs in hypertension.
    • Identify the molecular mechanisms that are induced by oxidative stress that initiate vascular damage and change vascular function
    • Develop improved in vitro and in vivo methods to measure oxidative stress in the tissues of animals and in human subjects
  • Support studies of mechanisms by which diuretics and other inexpensive antihypertensive agents reduce target organ damage independent of blood pressure control in patients with essential hypertension.

Publication Plans:

A manuscript in a peer-reviewed journal is planned in 2009.

NHLBI Contacts:

  • Winnie Barouch, Ph.D., barouchw@mail.nih.gov
  • Steve Goldman, Ph.D., goldmans@mail.nih.gov
  • Holly Krull, Ph.D.,krullh@mail.nih.gov
  • Terry Thrasher, Ph.D., thrashertn@nhlbi.nih.gov

Working Group Members

Chairs:

  • David Harrison, M.D., Emory University School of Medicine
  • Ernesto Schiffrin, M.D., Ph.D., McGill University

Members:

  • Lisa Cassis, PhD, University of Kentucky
  • Melinda Dwinell, PhD, Medical College of Wisconsin
  • Zahi Fayad, PhD, Mount Sinai School of Medicine
  • Virginia Huxley Ph.D., University of Missouri
  • Costantino Iadecola, MD, Weill Medical College of Cornell University
  • Warren Lockette, MD, University of California, San Diego
  • Gary Mitchell, MD, Cardiovascular Engineering, Inc.
  • Thomas Wang, MD, Massachusetts General Hospital
  • Karl Weber, MD, University of Tennessee Health Science Center
  • Christopher Wilcox, MD, PhD, Georgetown University Medical Center

Last updated: August 27, 2008

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