Measured and Genotyped Differences in Blood Pressure and the Usefulness of Precise Extreme Phenotypes Based on Cardiovascular Magnetic Resonance.

Hypertensive target organ damage (TOD) is of prognostic importance, and the presence of TOD is an independent predictor of cardiovascular risk, even more so if multiple target organs are involved. The classical view is that the presence of TOD signals the progression of uncomplicated hypertension to hypertensive disease. It is, therefore, surprising to realize that the causality and direction of hypertension-TOD are not clear in all cases (Figure). In this issue, Hendricks et al report findings from a group of genetically extreme individuals from the UK Biobank. The samples were chosen based on the extremes of 107 blood pressure (BP)-predicting variants. The number of variants included reflects the status of the field at the beginning of project; this list now contains around 1000 variants (http:// www.bloodpressuregenetics.org). The individuals represent the 2% to 3% extremes at both ends of the genetic distribution from 5596 individuals. The authors perform Mendelian randomization analyses for left ventricular (LV) mass, LV mass/volume ratio, radial and circumferential strain, and cardiac output; all phenotypes were ascertained using cardiovascular magnetic resonance imaging, a major effort of the UK Biobank that aims to evaluate 100 000 individuals using imaging data. Mendelian randomization studies are a highly useful tool for scientists and clinicians alike, permitting the investigation of the causality of effects. Several known risk alleles for an exposure variable (independent variable: BP in the current study) are assessed for their conjoint effect on an outcome variable, which was subclinical TOD herein: LV mass and other correlated phenotypes. The random allocation of alleles at birth permit slight modifications of the exposure variable, in randomized and blinded manner, that act throughout life. The power of the method stems from the duration of the effect (since birth) and large sample sizes typically used in epidemiological research. Because the modification of the exposure variable is small for typical complex traits such as BP, even when using a large number of genetic variables such as in the work by Hendricks et al, it is not surprising that many participants with high genetic BP load have normal or even low BP. The demonstration that the genetic BP risk score predicts LV mass, independent of pleiotropic effects, is proof that BP is a causal factor for LV mass and the other outcome variables predicted. There are previous data on the causality of BP elevation in the development of subclinical and clinical hypertensive TOD. However, the analysis by Hendricks et al is much more detailed for the LV and includes strain, an interesting deeper phenotype of LV function. Hendricks et al use two metrics of the exposure variable: the predicted change in BP due to the load of BP increasing genetic variants and the measured (phenotypic) load of BP that is based on office BP measures during the visits of the participants. Direct comparisons between the results derived using genetic BP and measured BP must be considered with caution because of the uncertainty of the effect size estimate of genetic BP. In general, the impact of the genetic BP on the LV phenotypes appears larger in the analyses by Hendricks et al, and this may be because of the lifelong exposure to the small increase in genetically determined BP. The results of the work by Hendricks et al are remarkable in several ways. First, they provide greater detail on the causal role of BP in LV hypertrophy and more subtle changes in myocardial remodeling based on analyses of strain; BP is confirmed to be the central causal player of LV morphological changes in hypertension. The exception is cardiac output, fundamentally related to BP as BP is the product of cardiac output and total peripheral resistance. There has been disagreement between generations of hypertension specialists on whether there is a significant change in cardiac output with chronic BP elevation. It is likely that the weakness of the association between BP and cardiac output (if any) has influenced the findings of Hendricks et al. Second, the work demonstrates that by using phenotypes with greater precision, the sample size required for a study can be largely reduced. Cardiovascular magnetic resonance-based variables have been previously shown to reduce the sample size requirements by an order of magnitude compared to that with techniques based on geometric assumptions. Third, analyses at the extremes of the genetic spectrum are of interest in BP genetics and can yield interesting results, as Hendricks et al show, with manageable work to acquire The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Geneva University Hospitals, Switzerland. Correspondence to Georg Ehret, Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Geneva 14 1211, Switzerland. Email georg.ehret@hcuge.ch Measured and Genotyped Differences in Blood Pressure and the Usefulness of Precise Extreme Phenotypes Based on Cardiovascular Magnetic Resonance