Abstract
Multiple factors contribute to the development of hypertension, including genetic factors and environmental exposures. Various pathophysiological mechanisms are at play in the pathogenesis of hypertension and this pathogenesis, by necessity, exhibits substantial variation at the level of the individual, as it depends on the relative contribution of inherited genes and individual lifetime environmental exposures. Over time, long-term compensatory mechanisms, including responses to either chronic hypertension or to therapeutic intervention, can only obscure the initiating mechanisms of disease. Acute compensating mechanisms can also mask initiating gene effects during or after an intervention, so that early phenotype assessments during the intervention may be more likely to detect the genetic initiators. Compensatory mechanisms, working over days, weeks or even years, will likely be variably effective in minimizing the expected blood pressure rise, making it difficult to detect genetic initiating mechanisms in cross-sectional, 'steady state', or 'in balance' studies. If the lifetime risk of hypertension indeed approaches 90%, the power to identify genetic factors can only decrease with duration of disease and treatment, and prediction of hypertension becomes of vanishing significance. With multiple factors at play, we cannot expect that all causes are mutually exclusive, but it is reasonable to assume that one of these mechanisms is predominant in the initiation of the disease in any one individual. Given the heterogeneity of essential hypertension argued above, it becomes evident that the chance of identifying genetic factors that contribute to disease development will be greatest if study subjects at highest genetic predisposition are observed during age ranges when heritability is at a maximum, using the correct phenotypes, measured in the correct tissues, during the correct time window. Genes found to be significant in such studies should be densely typed in clinical trials and large population studies to assess public health and clinical applications of the findings.