Endocrinology, Diabetes and Hypertension

Jonathan Williams, M.D.

Diastolic dysfunction is a cause of significant morbidity and mortality affecting approximately 5 million individuals in the United States. Relatively little is known about the pathophysiology of this condition leading to mostly empiric treatment with modest impact. We have shown that dietary sodium intake appears to modify normal diastolic function in humans and the mechanism responsible for this altered response is angiotensin II. These fundamental studies in normal volunteers raise the intriguing possibility that a dysfunctional response might be present in individuals with diastolic dysfunction thus resulting in an inability to respond appropriately to the high dietary sodium content of most Westernized diets. Planned studies will further delineate the role of angiotensin II in normal physiology, explore the relationship to central aortic stiffness, and finally investigate abnormal response characteristics in disease states (hypertensive heart disease, diabetes, others).

A second emphasis of our research group is to identify the genetic underpinnings of cardiovascular disease and risk, specifically in hypertension and insulin resistance/diabetes mellitus. We have developed a large (>1000 individuals) database of research subjects who have completed a detailed and controlled phenotyping protocol. To date, this program has been complemented by an extensive genotype database (>1000 SNPs in 40 genes related to cardiovascular disease). We are taking a rational, candidate gene approach to generate association studies quided by the phenotyping characteristics. Our over-riding aim is to not only identify genes associated with hypertension, but to identify the specific pathophysiologic mechanisms by which those genes cause hypertension.

1. Williams JS, Williams GH.  Fifty years of aldosterone.  J Clin Endo Metab, 2003; 88:2364-2372.
2. Williams JS, Williams GH, Jeunemaitre X, Hopkins PN, Conlin PR.  Influence of dietary sodium on the renin-angiotensin-aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria.  J H Hyperten 2005; 19:133-138.
3. Williams JS, Solomon SD, Crivaro M, Conlin PR.  Dietary sodium intake modulates myocardial relaxation responsiveness to angiotensin II.  J Lab Clin Med (In Press).