Systolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence

For the past several decades, hypertension has been defined as the blood pressure (BP) threshold at, or above which, the benefits of treating BP outweigh the harms of treatment as determined by randomized clinical trials. 1 However, while this notion of hypertension remains unchanged, the systolic BP (SBP) and diastolic BP (DBP) thresholds at which hypertension is diagnosed have gradually been reduced as clinical trials demonstrated the efficacy of antihypertensive medications on reducing cardiovascular events at increasingly lower BP cut-offs.2 The BP level at which treatment is no longer efficacious remains uncertain.Epidemiology studies play a major role in examining the associations between SBP and DBP and cardiovascular disease to inform the design of clinical trials, and BP thresholds and targets for treatment recommended by clinical guidelines.Observational studies found that the cardiovascular risk associated with BP may begin and rise in a linear manner at BP levels within ranges categorized by guidelines as "normal" or even "optimal".3,4 Furthermore, observational data suggest that the relative risk associated with a fixed increase in BP may be higher for younger individuals than older individuals, 3 and also reported conflicting data regarding sex differences in the relative risk of cardiovascular disease associated with hypertension.5,6 Nevertheless, interpretation of observational studies is tempered by the possibilities of residual confounding or reverse causation.Bolstered by the contemporary expansion of human genetic datasets, Mendelian Randomization (MR) analyses have gained popularity for prioritizing causal relationships with less risk for confounding.These analyses use naturally occurring genetic variations, randomly allocated and fixed at conception, as instrumental variables for the specific risk factor of interest and examine their potential causal effects on the desired outcome.MR analyses to date have found linear relationships between both physiologic SBP and DBP values and cardiovascular events among persons of largely European ancestry in