Epidemiology and clinical course of brain arteriovenous malformations (BAVM)

BAVMs are a rare but treatable cause of stroke from bleeding into the brain. These studies seek to define what the risks of neurologic damage are from both the natural history of the disease as well as from treatment of the disease. By knowing the balance between natural history and treatment risks in different subgroups of patients, more rational care can be offered to patients. Use of novel clinical trial methodologies and statistical modeling are used for this work. Parts of these studies are undertaken in conjunction with Kaiser-Permanente Northern California to examine aspects of natural history in a population-based cohort.

Adaptation of the cerebral circulation to chronic arterial hypotension

BAVMs induce low blood pressure in surrounding normal areas of brain. These clinical research studies examine the mechanisms by which normal brain can adapt to chronic decreased perfusion pressure. Preliminary evidence suggests involvement of some change in endothelial or neuronal nitric-oxide signalling. This work has been expanded to examine other clinical states which may share aspects of the same pathophysiology, such as cerebral hyperperfusion after percutaneous transluminal angioplasty and stenting of the arterial supply to the brain.

Endothelial biology of brain cerebrovascular malformations

By examining surgical specimens with the tools of molecular biology, the pathways associated with the development of human vascular malformations can be studied. Examples of these malformations include BAVMs, cavernous malformations, dural arteriovenous fistulas, and aneurysms. By use of cell culture systems and the development of small animal models, mechanistic studies can be undertaken to unravel the missteps in development or maturation which result in the human disease. From these studies, insights into better treatment strategies can be undertaken. A key system of interest is the Tie-2 / Angiopoietin signaling pathway.

Manipulation of brain angiogenesis

By manipulating the relative levels of various angiogenic factors, either by gene delivery, protein infusion or transgenic mouse backgrounds, we are studying ways to simulate vascular malformations of the brain and devise innovative strategies for the treatment of cerebral ischemia. The figures show focal hyperstimulation of angiogenesis using adenoviral vectors to deliver VEGF to brain. On the left, stereotactic delivery of Ad-lacZ to the basal ganglia results in lacZ staining; on the right, lectin staining showing proliferation of the capillary bed with the characteristic appearance of neo-angiogenesis.

Computational modeling of the cerebral circulation

By the development of computational models, it is often possible to take incomplete sets of experimental data and generate likely hypotheses to further test. Further, theoretical modeling of BAVM rupture risk can be used to improve selection of variables to develop for use in risk stratification purposes in clinical trials. A long-term goal of this line of inquiry is to eventually develop "patient-specific" physiologic models that can be used in conjunction with modern anatomic imaging for treatment planning and outcome assessment.

In collaboration with scientists from The Vascular Imaging Research Center, we are studying the effect of abnormal flow profiles that are present in cerebral aneurysms and arteriovenous malformations using magnetic resonance imaging and computational fluid dynamic modeling.

Genetics of cerebrovascular anomalies

The genetic defects in several familial or inherited types of stroke syndromes are known; much less well understood are the genetic defects in "sporadic" stroke syndromes. In collaboration with the UCSF Cardiovascular Research Institute and the Department of Genetics at Duke University, these studies are designed to define the interaction of subtle genetic alterations in key signaling pathways that are necessary for normal development and maintenance of the vascular endothelium. If these systems are not operating correctly, defects such as structural flaws in the blood vessel or a predisposition to clot formation may result.