High Systolic BP Causes Valve Disease, Genetic Study Suggests

Batya Swift Yasgur, MA, LSW

July 17, 2019

A person's lifetime exposure to elevated systolic blood pressure (BP) compared with a normal systolic BP, as reflected by a genetic risk score (GRS), almost triples the risk of developing some form of major valvular heart disease (VHD), a cohort study suggests.

Each genetically predicted 20 mm Hg increment in systolic BP in the analysis corresponded to a 3.6-fold higher risk for aortic stenosis, almost three times the risk for aortic regurgitation, and a 2-fold increased risk for mitral regurgitation.

Although links between elevated BP and valvular disease are well recognized, the evidence is mostly observational, which can't prove causation.

Nor do the new findings, but they provide strong evidence that elevated systolic BP actually leads to VHD, rather than the reverse, and suggest the prospect of primary VHD prevention.

The current analysis strengthens the evidence base by using Mendelian randomization, which relies on the natural, random allocation of gene variants associated with particular disorders; in this case, elevated BP.

The technique is admittedly "quasi-experimental" but is thought to mimic conventional prospective randomization, observe the authors of the analysis, led by Milad Nazarzadeh, MSc, from the University of Oxford, England, in their report published July 10 in JAMA Cardiology.

"Clinical practice guidelines currently make little reference to preventive strategies for major valvular disease," senior author Kazem Rahimi, MD, University of Oxford, England, told theheart.org | Medscape Cardiology.

Previous observational studies "by us and others" have demonstrated strong associations between elevated BP and risk for aortic stenosis, aortic regurgitation, and mitral regurgitation.

"However, in the absence of randomized trials, it was unclear whether the observed observations were causal," Rahimi said.

"This study highlights that high blood pressure should be considered a major risk factor, much as it is the case for heart attacks, stroke, and other cardiovascular diseases."

The analysis included 329,237 people genotyped in the UK Biobank database who were screened to include only whites of British descent to minimize potentially confounding allele variations by race and ethnicity, the group notes.

Participants joined the cohort from 2006 to 2010 at 22 centers in the United Kingdom; they ranged in age from 40 to 96 years at baseline, when their systolic BP was measured as the average of two readings. Of the total, 1.08% had a diagnosis of VHD.

The GRS scale was used in the study as a proxy for lifetime BP pattern, which reflected each participant's genotypic combined prevalence of any of 130 single-nucleotide polymorphisms (SNPs) known to influence blood pressure.

The SNPs were extracted from the UK Biobank imputation dataset; the authors selected ones shown to be associated with systolic BP in a genome-wide association meta-analysis. They were then used to develop the GRS that, when applied to individuals, became a model of genetic propensity for elevated systolic BP.

Indeed, the group notes, there was a "strong linear correlation" between the GRS and measured systolic BP, with a regression coefficient of 0.199 (P < .001).

Considering risk of aortic stenosis alone, each genetically based 20 mm Hg increment in systolic BP was associated with a more than three times increased odds of the valve disorder in an analysis adjusted for age and sex. Adjustment for additional variables only "minimally" changed the results, the group writes.

The odds of having any of the three forms of VHD increased almost three times per 20 mm Hg increase in systolic BP, with similar adjustment effects.

Table. Odds Ratio (OR) of VHD per Genetically Predicted 20 mm Hg Increment in Systolic BP

End points Adjusteda OR (95% CI) P value
Aortic valve stenosis 3.26 (1.50 - 7.10) .002
Aortic valve regurgitation 2.59 (0.75 - 8.92) .13>
Mitral valve regurgitation 2.19 (1.07 - 4.47) .03
Aortic valve stenosis or regurgitation or mitral valve regurgitation 2.85 (1.69 - 4.78) < .001

aAdjusted for age, sex, body mass index, UK Biobank assessment center, genotype measurement batch, alcohol intake frequency, smoking status, genetic kinship to other participants, "and 10 genetic principal components." CI = confidence interval

In sensitivity analyses, application of a GRS that excluded SNPs for "any of the established cardiovascular factors" did not greatly alter ORs for aortic stenosis, aortic regurgitation, or mitral regurgitation, the group notes. Nor did further adjustment for use of BP-lowering medications.

Although those checks bolster the robustness of the main analysis, overall there are some limitations, they write. The cohort was ethnically and racially narrow, which limits generalizability; and Mendelian randomization itself is a technique that relies on a number of assumptions.

Those assumptions include that the GRS reliably reflects measured systolic BP, that it's related to outcomes due only to elevated systolic BP, that it contains no confounders, and that the GRS and systolic BP relationship is strictly linear, the report notes.

Nevertheless, the Mendelian randomization model compared with conventional observational studies isn't prone to confounding and to the possibility of reverse causation, the group writes, and "thus suggests that BP-lowering treatment may be a useful strategy for prevention of VHD."

The study was funded by the National Institute for Health Research through the Oxford Biomedical Research Centre, the Oxford Martin School at the University of Oxford, the UKRI's Global Challenges Research Fund, and by the British Heart Foundation. Rahimi disclosed personal fees from PLoS Medicine and BMJ Heart outside the submitted work. Nazarzadeh has disclosed no relevant financial relationships.

JAMA Cardiology. Published online July 10, 2019. Abstract

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